1first Aid 2023 PARTE 5

www.medicalstudyzone.
com
www.medicalstudyzone.com
FIRST AID FOR
THE®
USMLE
STEP 1
2023
TAO LE, MD, MHS VIKAS BHUSHAN, MD
Founder, ScholarRx Founder, First Aid for the USMLE Step 1
Associate Clinical Professor, Department of Medicine Boracay, Philippines
University of Louisville School of Medicine
CONNIE QIU, MD, PhD ANUP CHALISE, MBBS, MS, MRCSEd

Resident, Department of Dermatology Kathmandu, Nepal
Johns Hopkins Hospital
PANAGIOTIS KAPARALIOTIS, MD CAROLINE COLEMAN, MD

University of Athens Medical School, Greece Resident, Department of Medicine
Emory University School of Medicine
KIMBERLY KALLIANOS, MD
Assistant Professor, Department of Radiology and Biomedical Imaging
University of California, San Francisco School of Medicine
New York / Chicago / San Francisco / Athens / London / Madrid / Mexico City
Milan / New Delhi / Singapore / Sydney / Toronto
FAS1_2023_00_Frontmatter.indd 1 11/18/22 5:38 PM

Contents
Contributing Authors vii General Acknowledgments xiii

Associate Authors viii How to Contribute xv
Faculty Advisors ix How to Use This Book xvii
Preface xi Selected USMLE Laboratory Values xviii
Special Acknowledgments xii First Aid Checklist for the USMLE Step 1 xx
SECTION I
` G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N 1
Introduction 2 Test-Taking Strategies 19

USMLE Step 1—The Basics 2 Clinical Vignette Strategies 21
Learning Strategies 11 If You Think You Failed 22
Timeline for Study 14 Testing Agencies 22
Study Materials 18 References 23
SECTION I SUPPLEMENT
` S P E C I A L S I T UAT I O N S 25
SECTION II
` HIGH-YIELD GENERAL PRINCIPLES 27
How to Use the Database 28 Pathology 201

Biochemistry 31 Pharmacology 227
Immunology 93 Public Health Sciences 255
Microbiology 121

SECTION III
` H I G H - Y I E L D O R G A N S YS T E M S 279
Approaching the Organ Systems 280 Neurology and Special Senses 499
Cardiovascular 283 Psychiatry 571
Endocrine 329 Renal 597
Gastrointestinal 363 Reproductive 631
Hematology and Oncology 409 Respiratory 679
Musculoskeletal, Skin, and Connective Tissue 449 Rapid Review 709
SECTION IV
` TO P - R AT E D R E V I E W R E S O U R C E S 741
How to Use the Database 742 Biochemistry 746

Question Banks 744 Cell Biology and Histology 746
Web and Mobile Apps 744 Microbiology and Immunology 746
Comprehensive 745 Pathology 747
Anatomy, Embryology, and Neuroscience 745 Pharmacology 747
Behavioral Science 746 Physiology 748
`
Abbreviations and Symbols 749 Index 775
Image Acknowledgments 757 About the Editors 828
vi

Selected USMLE Laboratory Values
* = Included in the Biochemical Profile (SMA-12)
Blood, Plasma, Serum Reference Range SI Reference Intervals
*Alanine aminotransferase (ALT, GPT at 30°C) 10–40 U/L 10–40 U/L

*Alkaline phosphatase 25–100 U/L 25–100 U/L
Amylase, serum 25–125 U/L 25–125 U/L
*Aspartate aminotransferase (AST, GOT at 30°C) 12–38 U/L 12–38 U/L
Bilirubin, serum (adult)
Total // Direct 0.1–1.0 mg/dL // 0.0–0.3 mg/dL 2–17 µmol/L // 0–5 µmol/L
*Calcium, serum (Total) 8.4–10.2 mg/dL 2.1–2.6 mmol/L
*Cholesterol, serum (Total) Rec: < 200 mg/dL < 5.2 mmol/L
*Creatinine, serum (Total) 0.6–1.2 mg/dL 53–106 µmol/L
Electrolytes, serum
Sodium (Na+) 136–146 mEq/L 136–146 mmol/L
Chloride (Cl–) 95–105 mEq/L 95–105 mmol/L
* Potassium (K ) 3.5–5.0 mEq/L 3.5–5.0 mmol/L
+
Bicarbonate (HCO3–) 22–28 mEq/L 22–28 mmol/L

Magnesium (Mg2+) 1.5–2 mEq/L 0.75–1.0 mmol/L
Gases, arterial blood (room air)
PO 2
75–105 mm Hg 10.0–14.0 kPa
PCO 2
33–45 mm Hg 4.4–5.9 kPa
pH 7.35–7.45 [H+] 36–44 nmol/L
*Glucose, serum Fasting: 70–100 mg/dL 3.8–6.1 mmol/L
Growth hormone − arginine stimulation Fasting: < 5 ng/mL < 5 µg/L
Provocative stimuli: > 7 ng/mL > 7 µg/L
Osmolality, serum 275–295 mOsmol/kg H2O 275–295 mOsmol/kg H2O
*Phosphorus (inorganic), serum 3.0–4.5 mg/dL 1.0–1.5 mmol/L
Prolactin, serum (hPRL) Male: < 17 ng/mL < 17 µg/L
Female: < 25 ng/mL < 25 µg/L
*Proteins, serum
Total (recumbent) 6.0–7.8 g/dL 60–78 g/L
Albumin 3.5–5.5 g/dL 35–55 g/L
Globulins 2.3–3.5 g/dL 23–35 g/L
Thyroid-stimulating hormone, serum or plasma 0.4–4.0 µU/mL 0.4–4.0 mIU/L
*Urea nitrogen, serum (BUN) 7–18 mg/dL 25–64 nmol/L
*Uric acid, serum 3.0–8.2 mg/dL 0.18–0.48 mmol/L
(continues)
xviii

Cerebrospinal Fluid Reference Range SI Reference Intervals
Cell count 0–5/mm3 0–5 × 106/L

Glucose 40–70 mg/dL 2.2–3.9 mmol/L
Proteins, total < 40 mg/dL < 0.40 g/L
Hematologic
Erythrocyte count Male: 4.3–5.9 million/mm3 4.3–5.9 × 1012/L

Female: 3.5–5.5 million/mm3 3.5–5.5 × 1012/L
Erythrocyte sedimentation rate (Westergen) Male: 0–15 mm/hr 0–15 mm/hr
Female: 0–20 mm/hr 0–20 mm/hr
Hematocrit Male: 41–53% 0.41–0.53
Female: 36–46% 0.36–0.46
Hemoglobin, blood Male: 13.5–17.5 g/dL 135–175 g/L
Female: 12.0–16.0 g/dL 120–160 g/L
Hemoglobin, plasma < 4 mg/dL < 0.62 µmol/L
Leukocyte count and differential
Leukocyte count 4,500–11,000/mm3 4.5–11.0 × 109/L
Segmented neutrophils 54–62% 0.54–0.62
Band forms 3–5% 0.03–0.05
Eosinophils 1–3% 0.01–0.03
Basophils 0–0.75% 0–0.0075
Lymphocytes 25–33% 0.25–0.33
Monocytes 3–7% 0.03–0.07
Mean corpuscular hemoglobin 25–35 pg/cell 0.39–0.54 fmol/cell
Mean corpuscular hemoglobin concentration 31%–36% Hb/cell 4.8–5.6 mmol Hb/L
Mean corpuscular volume 80–100 μm 3
80–100 fL
Partial thromboplastin time (activated) 25–40 sec 25–40 sec
Platelet count 150,000–400,000/mm3 150–400 × 109/L
Prothrombin time 11–15 sec 11–15 sec
Reticulocyte count 0.5–1.5% of RBCs 0.005–0.015
Urine
Creatinine clearance Male: 97–137 mL/min 97–137 mL/min

Female: 88–128 mL/min 88–128 mL/min
Osmolality 50–1200 mOsmol/kg H2O 50–1200 mOsmol/kg H2O
Proteins, total < 150 mg/24 hr < 0.15 g/24 hr
Other
Body mass index Adult: 19–25 kg/m2 19–25 kg/m2
xix

First Aid
First Aid Checklist Checklist
for the USMLEfor
Stepthe
1 USMLE Step 1
This is an example of how you might use the information in Section I to prepare for the USMLE Step 1.
This
Referistoan example oftopics
corresponding how you might Iuse
in Section for the
moreinformation
details. in Section I to prepare for the USMLE
Step 1. Refer to corresponding topics in Section I for more details.
Years Prior Use top-rated review resources for first-year medical school courses.
Ask for advice from those who have recently taken the USMLE Step 1.
Months Prior Review computer test format and registration information.

Register six months in advance.
Carefully verify name and address printed on scheduling permit. Make sure
the name on scheduling permit matches the name printed on your photo ID.
Go online for test date ASAP.
Set up a realistic timeline for study. Cover less crammable subjects first.
Evaluate and choose study materials (review books, question banks).
Use a question bank to simulate the USMLE Step 1 to pinpoint strengths and
weaknesses in knowledge and test-taking skills from early on.
Weeks Prior Do test simulations in question banks.

Assess how close you are to your goal.
Pinpoint remaining weaknesses. Stay healthy (eg, exercise, sleep).
Verify information on admission ticket (eg, location, date).
One Week Prior Remember comfort measures (eg, loose clothing, earplugs).
Work out test site logistics (eg, location, transportation, parking, lunch).
Print or download your Scheduling Permit and Scheduling Confirmation
to your phone.
One Day Prior Relax.

Lightly review short-term material if necessary. Skim high-yield facts.
Get a good night’s sleep.
Day of Exam Relax.

Eat breakfast.
Minimize bathroom breaks during exam by avoiding excessive morning
caffeine.
After Exam Celebrate, regardless of how well you feel you did.
Send feedback to us on our website at www.firstaidteam.com
or at firstaid@scholarrx.com.
xx

SECTION I
Guide to Efficient
Exam Preparation
“One important key to success is self-confidence. An important key to self- ` Introduction2

confidence is preparation.”
—Arthur Ashe ` USMLE Step 1—The
Basics2
“Wisdom is not a product of schooling but of the lifelong attempt to
acquire it.” ` Learning Strategies 11
—Albert Einstein
` Timeline for Study 14
“Finally, from so little sleeping and so much reading, his brain dried up
and he went completely out of his mind.” ` Study Materials 18
—Miguel de Cervantes Saavedra, Don Quixote
` Test-Taking
“Sometimes the questions are complicated and the answers are simple.” Strategies19
—Dr. Seuss
` Clinical Vignette
“He who knows all the answers has not been asked all the questions.” Strategies21
—Confucius
` If You Think You
“The expert in anything was once a beginner.”
Failed22
—Helen Hayes
“It always seems impossible until it’s done.” ` Testing Agencies 22

—Nelson Mandela
` References23
FAS1_2023_00_Section_I.indd 1 11/18/22 7:31 AM

2 SECTION I Guide to Efficient Exam Preparation
INTRODUCTION
`
Relax.
This section is intended to make your exam preparation easier, not harder.
Our goal is to reduce your level of anxiety and help you make the most
of your efforts by helping you understand more about the United States
Medical Licensing Examination, Step 1 (USMLE Step 1). As a medical
student, you are no doubt familiar with taking standardized examinations
and quickly absorbing large amounts of material. When you first confront
the USMLE Step 1, however, you may find it all too easy to become
sidetracked from your goal of studying with maximal effectiveness. Common
mistakes that students make when studying for Step 1 include the following:
Starting to study (including First Aid) too late

Starting to study intensely too early and burning out
Starting to prepare for boards before creating a knowledge foundation
Using inefficient or inappropriate study methods
Buying the wrong resources or buying too many resources
Buying only one publisher’s review series for all subjects
Not using practice examinations to maximum benefit
Not understanding how scoring is performed or what the result means
Not using review books along with your classes
Not analyzing and improving your test-taking strategies
Getting bogged down by reviewing difficult topics excessively
Studying material that is rarely tested on the USMLE Step 1
Failing to master certain high-yield subjects owing to overconfidence
Using First Aid as your sole study resource
Trying to prepare for it all alone
In this section, we offer advice to help you avoid these pitfalls and be more
productive in your studies.
USMLE STEP 1—THE BASICS

`
` The test at a glance: The USMLE Step 1 is the first of three examinations that you would
8-hour exam normally pass in order to become a licensed physician in the United
Up to a total of 280 multiple choice items States. The USMLE is a joint endeavor of the National Board of Medical
7 test blocks (60 min/block) Examiners (NBME) and the Federation of State Medical Boards (FSMB).
Up to 40 test items per block The USMLE serves as the single examination system domestically and
45 minutes of break time, plus another 15 internationally for those seeking medical licensure in the United States.
if you skip the tutorial The Step 1 exam includes test items that can be grouped by the organiza-
tional constructs outlined in Table 1 (in order of tested frequency). In late
2020, the USMLE increased the number of items assessing communication
skills. While pharmacology is still tested, they are focusing on drug mecha-
nisms rather than on pharmacotherapy. You will not be required to identify
the specific medications indicated for a specific condition. Instead, you will
be asked more about drug mechanisms and side effects.

Guide to Efficient Exam Preparation SECTION I 3
T A B L E 1 . Frequency of Various Constructs Tested on the USMLE Step 1.1,*
Competency Range, % System Range, %
Medical knowledge: applying foundational 60–70 General principles 12–16
science concepts
Patient care: diagnosis 20–25 Behavioral health & nervous systems/special senses 9–13
Communication and interpersonal skills 6–9 Respiratory & renal/urinary systems 9–13
Practice-based learning & improvement 4–6 Reproductive & endocrine systems 9–13
Discipline Range, % Blood & lymphoreticular/immune systems 7–11
Pathology 44–52 Multisystem processes & disorders 6–10
Physiology 25–35 Musculoskeletal, skin & subcutaneous tissue 6–10
Pharmacology 15–22 Cardiovascular system 5–9
Biochemistry & nutrition 14–24 Gastrointestinal system 5–9
Microbiology 10–15 Biostatistics & epidemiology/population health 4–6
Immunology 6–11 Social sciences: communication skills/ethics 6–9
Gross anatomy & embryology 11–15
Histology & cell biology 8–13
Behavioral sciences 8–13
Genetics 5–9
*Percentages are subject to change at any time. www.usmle.org
How Is the Computer-Based Test (CBT) Structured?
The CBT Step 1 exam consists of one “optional” tutorial/simulation block

and seven “real” question blocks of up to 40 questions per block with no
more than 280 questions in total, timed at 60 minutes per block. A short
11-question survey follows the last question block. The computer begins the
survey with a prompt to proceed to the next block of questions.
Once an examinee finishes a particular question block on the CBT, he or

she must click on a screen icon to continue to the next block. Examinees
cannot go back and change their answers to questions from any previously
completed block. However, changing answers is allowed within a block of
questions as long as the block has not been ended and if time permits.
What Is the CBT Like?
Given the unique environment of the CBT, it’s important that you become
familiar ahead of time with what your test-day conditions will be like. You
can access a 15-minute tutorial and practice blocks at http://orientation.
nbme.org/Launch/USMLE/STPF1. This tutorial interface is the same as
the one you will use in the exam; learn it now and you can skip taking it
during the exam, giving you up to 15 extra minutes of break time. You can
gain experience with the CBT format by taking the 120 practice questions (3
blocks with 40 questions each) available online for free (https://www.usmle.
org/prepare-your-exam) or by signing up for a practice session at a test center
for a fee.

For security reasons, examinees are not allowed to bring any personal
electronic equipment into the testing area. This includes both digital and
analog watches, cell phones, tablets, and calculators. Examinees are also
prohibited from carrying in their books, notes, pens/pencils, and scratch
paper (laminated note boards and fine-tip dry erase pens will be provided
for use within the testing area). Food and beverages are also prohibited
in the testing area. The testing centers are monitored by audio and video
surveillance equipment. However, most testing centers allot each examinee
a small locker outside the testing area in which he or she can store snacks,
beverages, and personal items.
` Keyboard shortcuts:
Questions are typically presented in multiple choice format, with 4 or more
A, B, etc—letter choices
possible answer options. There is a countdown timer on the lower left corner
Esc—exit pop-up Calculator and Notes
of the screen as well. There is also a button that allows the examinee to mark
windows
a question for review. If a given question happens to be longer than the
screen, a scroll bar will appear on the right, allowing the examinee to see the
rest of the question. Regardless of whether the examinee clicks on an answer
choice or leaves it blank, he or she must click the “Next” button to advance
to the next question.
The USMLE features a small number of media clips in the form of audio
` Heart sounds are tested via media questions. and/or video. There may even be a question with a multimedia heart sound
Make sure you know how different heart simulation. In these questions, a digital image of a torso appears on the
diseases sound on auscultation. screen, and the examinee directs a digital stethoscope to various auscultation
points to listen for heart and breath sounds. The USMLE orientation
materials include several practice questions in these formats. During the
exam tutorial, examinees are given an opportunity to ensure that both the
` Be sure to test your headphones during the
audio headphones and the volume are functioning properly. If you are
tutorial.
already familiar with the tutorial and planning on skipping it, first skip ahead
to the section where you can test your headphones. After you are sure the
headphones are working properly, proceed to the exam.
` Familiarize yourself with the commonly

The examinee can call up a window displaying normal laboratory values.
tested lab values (eg, Hb, WBC, Ca2+, Na+,
In order to do so, he or she must click the “Lab” icon on the top part of
K+).
the screen. Afterward, the examinee will have the option to choose between
“Blood,” “Cerebrospinal,” “Hematologic,” or “Sweat and Urine.” The
normal values screen may obscure the question if it is expanded. The
examinee may have to scroll down to search for the needed lab values. You
` Illustrations on the test include: might want to memorize some common lab values so you spend less time on
Gross specimen photos questions that require you to analyze these.
Histology slides
The CBT interface provides a running list of questions on the left part of the
Medical imaging (eg, x-ray, CT, MRI)
screen at all times. The software also permits examinees to highlight or cross
Electron micrographs
out information by using their mouse. There is a “Notes” icon on the top
Line drawings
part of the screen that allows students to write notes to themselves for review
at a later time. Finally, the USMLE has recently added new functionality
including text magnification and reverse color (white text on black
background). Being familiar with these features can save time and may help
you better view and organize the information you need to answer a question.

For those who feel they might benefit, the USMLE offers an opportunity
to take a simulated test, or “CBT Practice Session” at a Prometric center.
Students are eligible to register for this three-and-one-half-hour practice
session after they have received their scheduling permit.
The same USMLE Step 1 sample test items (120 questions) available ` You can take a shortened CBT practice test at
on the USMLE website are used at these sessions. No new items will be a Prometric center.
presented. The practice session is available at a cost of $75 ($155 if taken
outside of the US and Canada) and is divided into a short tutorial and three
1-hour blocks of ~40 test items each. Students receive a printed percent-
correct score after completing the session. No explanations of questions are
provided.
You may register for a practice session online at www.usmle.org. A separate

scheduling permit is issued for the practice session. Students should allow
two weeks for receipt of this permit.
How Do I Register to Take the Exam?
Prometric test centers offer Step 1 on a year-round basis, except for the first ` The Prometric website will display a calendar
two weeks in January and major holidays. Check with the test center you with open test dates.
want to use before making your exam plans.
US students can apply to take Step 1 at the NBME website. This application
allows you to select one of 12 overlapping three-month blocks in which to be
tested (eg, April–May–June, June–July–August). Choose your three-month
eligibility period wisely. If you need to reschedule outside your initial three-
month period, you can request a one-time extension of eligibility for the next
contiguous three-month period, and pay a rescheduling fee. The application
also includes a photo ID form that must be certified by an official at your
medical school to verify your enrollment. After the NBME processes your
application, it will send you a scheduling permit.
The scheduling permit you receive from the NBME will contain your USMLE
identification number, the eligibility period in which you may take the exam,
and two additional numbers. The first of these is known as your “scheduling
number.” You must have this number in order to make your exam appointment
with Prometric. The second number is known as the “candidate identification
number,” or CIN. Examinees must enter their CINs at the Prometric
workstation in order to access their exams. However, you will not be allowed
to bring your permit into the exam and will be asked to copy your CIN onto
your scratch paper. Prometric has no access to the codes. Make sure to bring
a paper or electronic copy of your permit with you to the exam! Also bring
an unexpired, government-issued photo ID that includes your signature (such
as a driver’s license or passport). Make sure the name on your photo ID exactly
matches the name that appears on your scheduling permit.

` Be familiar with Prometric’s policies for Once you receive your scheduling permit, you may access the Prometric
cancellation and rescheduling due to website or call Prometric’s toll-free number to arrange a time to take the
COVID-19. exam. You may contact Prometric two weeks before the test date if you
want to confirm identification requirements. Be aware that your exam may
be canceled because of circumstances related to the COVID-19 pandemic
or other unforeseen events. If that were to happen, you should receive an
email from Prometric containing notice of the cancellation and instructions
on rescheduling. Visit www.prometric.com for updates regarding their
COVID-19 cancellation and rescheduling policies.
Although requests for taking the exam may be completed more than six months
before the test date, examinees will not receive their scheduling permits earlier
than six months before the eligibility period. The eligibility period is the three-
month period you have chosen to take the exam. Most US medical students
` Test scheduling is done on a “first-come,
attending a school which uses the two-year preclerkship curriculum choose
first-served” basis. It’s important to schedule
the April–June or June–August period. Most US medical students attending
an exam date as soon as you receive your
a school which uses the 18-month preclerkship curriculum choose the
scheduling permit.
December–February or January–March period.
What If I Need to Reschedule the Exam?
You can change your test date and/or center by contacting Prometric at
1-800-MED-EXAM (1-800-633-3926) or www.prometric.com. Make sure to
have your CIN when rescheduling. If you are rescheduling by phone, you must
speak with a Prometric representative; leaving a voicemail message will not
suffice. To avoid a rescheduling fee, you will need to request a change at least
31 calendar days before your appointment. Please note that your rescheduled
test date must fall within your assigned three-month eligibility period.
When Should I Register for the Exam?

` Register six months in advance for seating
and scheduling preference. You should plan to register as far in advance as possible ahead of your
desired test date (eg, six months), but, depending on your particular test
center, new dates and times may open closer to the date. Scheduling early
will guarantee that you will get either your test center of choice or one
within a 50-mile radius of your first choice. For most US medical students,
the desired testing window correlates with the end of the preclerkship
curriculum, which is around June for schools on a two-year preclerkship
schedule, and around January for schools on an 18-month schedule. Thus
US medical students should plan to register before January in anticipation of
a June test date, or before August in anticipation of a January test date. The
timing of the exam is more flexible for IMGs, as it is related only to when
they finish exam preparation. Talk with upperclassmen who have already
taken the test so you have real-life experience from students who went
through a similar curriculum, then formulate your own strategy.

Where Can I Take the Exam?
Your testing location is arranged with Prometric when you book your test
date (after you receive your scheduling permit). For a list of Prometric
locations nearest you, visit www.prometric.com.
How Long Will I Have to Wait Before I Get My Result?
The USMLE reports results in three to four weeks, unless there are delays
in processing. Examinees will be notified via email when their results are
available. By following the online instructions, examinees will be able
to view, download, and print their exam report online for ~120 days after
notification, after which results can only be obtained through requesting an
official USMLE transcript. Additional information about results reporting
timetables and accessibility is available on the official USMLE website.
Between 2020 and 2021, Step 1 pass rates dropped from 97% to 95% across
US/Canadian schools and from 83% to 77% across non-US/Canadian
schools (see Table 2).
What About Time?

` Gain extra break time by skipping the
Time is of special interest on the CBT exam. Here’s a breakdown of the tutorial, or utilize the tutorial time to add
exam schedule: personal notes to your scratch paper.
15 minutes Tutorial (skip if familiar with test format and features)

7 hours Seven 60-minute question blocks
45 minutes Break time (includes time for lunch)
The computer will keep track of how much time has elapsed on the exam.
However, the computer will show you only how much time you have
remaining in a given block. Therefore, it is up to you to determine if you
are pacing yourself properly (at a rate of approximately one question per 90
seconds).
The computer does not warn you if you are spending more than your allotted
time for a break. You should therefore budget your time so that you can take a
short break when you need one and have time to eat. You must be especially
careful not to spend too much time in between blocks (you should keep track
of how much time elapses from the time you finish a block of questions to the
time you start the next block). After you finish one question block, you’ll need
to click to proceed to the next block of questions. If you do not click within
30 seconds, you will automatically be entered into a break period.
Break time for the day is 45 minutes, but you are not required to use all of
it, nor are you required to use any of it. You can gain extra break time (but
not extra time for the question blocks) by skipping the tutorial or by finishing
` Be careful to watch the clock on your break
a block ahead of the allotted time. Any time remaining on the clock when
time.
you finish a block gets added to your remaining break time. Once a new
question block has been started, you may not take a break until you have
reached the end of that block. If you do so, this will be recorded as an
“unauthorized break” and will be reported on your final exam report.

Finally, be aware that it may take a few minutes of your break time to “check
out” of the secure resting room and then “check in” again to resume testing,
so plan accordingly. The “check-in” process may include fingerprints,
pocket checks, and metal detector scanning. Some students recommend
pocketless clothing on exam day to streamline the process.
If I Freak Out and Leave, What Happens to My Exam?
Your scheduling permit shows a CIN that you will need to enter to start your
exam. Entering the CIN is the same as breaking the seal on a test book, and
you are considered to have started the exam when you do so. However, no
result will be reported if you do not complete the exam. If you leave at any
time after starting the test, or do not open every block of your test, your test
will not be scored and will be reported as incomplete. Incomplete results
count toward the maximum of four attempts for each Step exam. Although
a pass or fail result is not posted for incomplete tests, examinees may still be
offered an option to request that their scores be calculated and reported if
they desire; unanswered questions will be scored as incorrect.
The exam ends when all question blocks have been completed or when
their time has expired. As you leave the testing center, you will receive a
printed test-completion notice to document your completion of the exam.
To receive an official score, you must finish the entire exam.
What Types of Questions Are Asked?
` Nearly three fourths of Step 1 questions begin

All questions on the exam are one-best-answer multiple choice items.
with a description of a patient.
Most questions consist of a clinical scenario or a direct question followed
by a list of four or more options. You are required to select the single best
T A B L E 2 . Passing Rates for the 2020-2021 USMLE Step 1.2

2020 2021
No. Tested % Passing No. Tested % Passing
Allopathic 1st takers 19,772 98% 22,280 96%
Repeaters 571 67% 798 66%
Allopathic total 20,343 95% 23,078 95%
Osteopathic 1st takers 5,235 96% 5,309 94%
Repeaters 39 74% 56 75%
Osteopathic total 5,274 95% 5,365 94%
Total US/Canadian 25,617 97% 28,443 95%
IMG 1st takers 11,742 87% 16,952 82%
Repeaters 1,375 50% 2,258 45%
IMG total 13,117 83% 19,210 77%
Total Step 1 examinees 38,734 92% 47,653 87%

answer among the options given. There are no “except,” “not,” or matching
questions on the exam. A number of options may be partially correct, in
which case you must select the option that best answers the question or
completes the statement. Additionally, keep in mind that experimental
questions may appear on the exam, which do not affect your exam result.
How Is the Test Scored?
The USMLE transitioned to a pass/fail scoring system for Step 1 on January 26,
2022. Examinees now receive an electronic report that will display the outcome
of either “Pass” or “Fail.” Failing reports include a graphic depiction of the
distance between the examinee’s score and the minimum passing standard
as well as content area feedback. Feedback for the content area shows the
examinee’s performance relative to examinees with a low pass (lower, same, or
higher) and should be used to guide future study plans. Passing exam reports
only displays the outcome of “Pass,” along with a breakdown of topics covered
on that individual examination (which will closely mirror the frequencies listed
in Table 1). Note that a number of questions are experimental and are not
counted toward or against the examinee’s performance.
Examinees who took the test before the transition to pass/fail reporting received
an electronic report that includes the examinee’s pass/fail status, a three-
digit test score, a bar chart comparing the examinee’s performance in each
content area with their overall Step 1 performance, and a graphic depiction
of the examinee’s performance by physician task, discipline, and organ system.
Changes will not be made to transcripts containing three-digit test scores.
The USMLE does not report the minimum number of correct responses
needed to pass, but estimates that it is approximately 60%. The USMLE ` Depending on the resource used, practice
may update exam result reporting in the future, so please check the USMLE questions may be easier than the actual
website or www.firstaidteam.com for updates. exam.
Official NBME/USMLE Resources
The NBME offers a Comprehensive Basic Science Examination (CBSE) for

practice that is a shorter version of the Step 1. The CBSE contains four blocks
of 50 questions each and covers material that is typically learned during the
basic science years. CBSE scores represent the percent of content mastered and
show an estimated probability of passing Step 1. Many schools use this test to
gauge whether a student is expected to pass Step 1. If this test is offered by your
school, it is usually conducted at the end of regular didactic time before any
dedicated Step 1 preparation. If you do not encounter the CBSE before your
dedicated study time, you need not worry about taking it. Use the information
to help set realistic goals and timetables for your success.

The NBME also offers six forms of Comprehensive Basic Science Self-
Assessment (CBSSA). Students who prepared for the exam using this web-
based tool reported that they found the format and content highly indicative
of questions tested on the actual exam. In addition, the CBSSA is a fair
predictor of historical USMLE performance. The test interface, however,
does not match the actual USMLE test interface, so practicing with these
forms alone is not advised.
The CBSSA exists in two formats: standard-paced and self-paced, both of

which consist of four sections of 50 questions each (for a total of 200 multiple
choice items). The standard-paced format allows the user up to 75 minutes
to complete each section, reflecting time limits similar to the actual exam.
By contrast, the self-paced format places a 5-hour time limit on answering all
multiple choice questions. Every few years, new forms are released and older
ones are retired, reflecting changes in exam content. Therefore, the newer
exams tend to be more similar to the actual Step 1, and scores from these
exams tend to provide a better estimation of exam day performance.
Keep in mind that this bank of questions is available only on the web. The
NBME requires that users start and complete the exam within 90 days of
purchase. Once the assessment has begun, users are required to complete
the sections within 20 days. Following completion of the questions, the
CBSSA provides a performance profile indicating the user’s relative
strengths and weaknesses, much like the report profile for the USMLE Step
1 exam. In addition to the performance profile, examinees will be informed
of the number of questions answered incorrectly. You will have the ability
to review the text of all questions with detailed explanations. The NBME
charges $60 for each assessment, payable by credit card or money order. For
more information regarding the CBSE and the CBSSA, visit the NBME’s
website at www.nbme.org.
The NBME scoring system is weighted for each assessment exam. While
some exams seem more difficult than others, the equated percent correct
reported takes into account these inter-test differences. Also, while
many students report seeing Step 1 questions “word-for-word” out of the
assessments, the NBME makes special note that no live USMLE questions
are shown on any NBME assessment.
Lastly, the International Foundations of Medicine (IFOM) offers a Basic

Science Examination (BSE) practice exam at participating Prometric test
centers for $200. Students may also take the self-assessment test online for
$35 through the NBME’s website. The IFOM BSE is intended to determine
an examinee’s relative areas of strength and weakness in general areas of
basic science—not to predict performance on the USMLE Step 1 exam—
and the content covered by the two examinations is somewhat different.
However, because there is substantial overlap in content coverage and many
IFOM items were previously used on the USMLE Step 1, it is possible to
roughly project IFOM performance onto the historical USMLE Step 1
score scale. More information is available at http://www.nbme.org/ifom/.

LEARNING STRATEGIES
`
Many students feel overwhelmed during the preclinical years and struggle to
find an effective learning strategy. Table 3 lists several learning strategies you
can try and their estimated effectiveness for Step 1 preparation based on the
literature (see References). These are merely suggestions, and it’s important
to take your learning preferences into account. Your comprehensive
learning approach will contain a combination of strategies (eg, elaborative
interrogation followed by practice testing, mnemonics review using spaced ` The foundation of knowledge you build
repetition, etc). Regardless of your choice, the foundation of knowledge during your basic science years is the most
you build during your basic science years is the most important resource for important resource for success on the USMLE
success on the USMLE Step 1. Step 1.
T A B L E 3 . Effective Learning Strategies.

Efficacy Strategy Example Resources
High efficacy Practice testing UWorld Qbank
(retrieval practice) NBME Self-Assessments
USMLE-Rx QMax
Amboss Qbank
Distributed practice USMLE-Rx Flash Facts
Anki
Firecracker
Memorang
Osmosis
Moderate Mnemonics Pre-made:
efficacy SketchyMedical
Picmonic
Self-made:
Mullen Memory
Elaborative interrogation/
self-explanation
Concept mapping Coggle
FreeMind
XMind
MindNode
Low efficacy Rereading
Highlighting/underlining
Summarization

HIGH EFFICACY
Practice Testing
Also called “retrieval practice,” practice testing has both direct and indirect
benefits to the learner.4 Effortful retrieval of answers does not only identify
weak spots—it directly strengthens long-term retention of material.5 The
` Research has shown a positive correlation more effortful the recall, the better the long-term retention. This advantage
between the number of boards-style practice has been shown to result in higher test scores and GPAs.6 In fact, research
questions completed and Step 1 performance has shown a positive correlation between the number of boards-style practice
among medical students. questions completed and Step 1 performance among medical students.7
Practice testing should be done with “interleaving” (mixing of questions

from different topics in a single session). Question banks often allow you to
intermingle topics. Interleaved practice helps learners develop their ability to
focus on the relevant concept when faced with many possibilities. Practicing
topics in massed fashion (eg, all cardiology, then all dermatology) may seem
intuitive, but there is strong evidence that interleaving correlates with longer-
term retention and increased student achievement, especially on tasks that
involve problem solving.5
In addition to using question banks, you can test yourself by arranging your
notes in a question-answer format (eg, via flash cards). Testing these Q&As in
random order allows you to reap the benefit of interleaved practice. Bear in
mind that the utility of practice testing comes from the practice of information
retrieval, so simply reading through Q&As will attenuate this benefit.
Distributed Practice
Also called “spaced repetition,” distributed practice is the opposite of massed

practice or “cramming.” Learners review material at increasingly spaced out
intervals (days to weeks to months). Massed learning may produce more
short-term gains and satisfaction, but learners who use distributed practice
have better mastery and retention over the long term.5,9
Flash cards are a simple way to incorporate both distributed practice and
practice testing. Studies have linked spaced repetition learning with flash
` Studies have linked spaced repetition cards to improved long-term knowledge retention and higher exam scores.6,8,10
learning with flash cards to improved long- Apps with automated spaced-repetition software (SRS) for flash cards exist for
term knowledge retention and higher exam smartphones and tablets, so the cards are accessible anywhere. Proceed with
scores. caution: there is an art to making and reviewing cards. The ease of quickly
downloading or creating digital cards can lead to flash card overload (it is
unsustainable to make 50 flash cards per lecture!). Even at a modest pace,
the thousands upon thousands of cards are too overwhelming for Step 1
preparation. Unless you have specific high-yield cards (and have checked
the content with high-yield resources), stick to pre-made cards by reputable
sources that curate the vast amount of knowledge for you.
If you prefer pen and paper, consider using a planner or spreadsheet to

organize your study material over time. Distributed practice allows for

some forgetting of information, and the added effort of recall over time
strengthens the learning.
MODERATE EFFICACY
Mnemonics
A “mnemonic” refers to any device that assists memory, such as acronyms,

mental imagery (eg, keywords with or without memory palaces), etc. Keyword
mnemonics have been shown to produce superior knowledge retention
when compared with rote memorization in many scenarios. However, they
are generally more effective when applied to memorization-heavy, keyword-
friendly topics and may not be broadly suitable.5 Keyword mnemonics may
not produce long-term retention, so consider combining mnemonics with
distributed, retrieval-based practice (eg, via flash cards with SRS).
Self-made mnemonics may have an advantage when material is simple and

keyword friendly. If you can create your own mnemonic that accurately
represents the material, this will be more memorable. When topics are
complex and accurate mnemonics are challenging to create, pre-made
mnemonics may be more effective, especially if you are inexperienced at
creating mnemonics.11
Elaborative Interrogation/Self-Explanation
Elaborative interrogation (“why” questions) and self-explanation (general ` Elaborative interrogation and self-
questioning) prompt learners to generate explanations for facts. When explanation prompt learners to generate
reading passages of discrete facts, consider using these techniques, which explanations for facts, which improves recall
have been shown to be more effective than rereading (eg, improved recall and problem solving.
and better problem-solving/diagnostic performance).5,12,13
Concept Mapping
Concept mapping is a method for graphically organizing knowledge, with

concepts enclosed in boxes and lines drawn between related concepts.
Creating or studying concept maps may be more effective than other
activities (eg, writing or reading summaries/outlines). However, studies have
reached mixed conclusions about its utility, and the small size of this effect
raises doubts about its authenticity and pedagogic significance.14
LOW EFFICACY
Rereading
While the most commonly used method among surveyed students,

rereading has not been shown to correlate with grade point average.9 Due to
its popularity, rereading is often a comparator in studies on learning. Other

strategies that we have discussed (eg, practice testing) have been shown to be
significantly more effective than rereading.
Highlighting/Underlining
Because this method is passive, it tends to be of minimal value for learning

and recall. In fact, lower-performing students are more likely to use these
techniques.9 Students who highlight and underline do not learn how
to actively recall learned information and thus find it difficult to apply
knowledge to exam questions.
Summarization
While more useful for improving performance on generative measures (eg,

free recall or essays), summarization is less useful for exams that depend on
recognition (eg, multiple choice). Findings on the overall efficacy of this
method have been mixed.5
TIMELINE FOR STUDY

`
Before Starting
Your preparation for the USMLE Step 1 should begin when you enter
medical school. Organize and commit to studying from the beginning so
that when the time comes to prepare for the USMLE, you will be ready with
a strong foundation.
` Customize your schedule. Tackle your weakest Make a Schedule

section first.
After you have defined your goals, map out a study schedule that is consistent
with your objectives, your vacation time, the difficulty of your ongoing
coursework, and your family and social commitments. Determine whether you
want to spread out your study time or concentrate it into 14-hour study days in
the final weeks. Then factor in your own history in preparing for standardized
examinations (eg, SAT, MCAT). Talk to students at your school who have
recently taken Step 1. Ask them for their study schedules, especially those who
have study habits and goals similar to yours. Sample schedules can be found at
https://firstaidteam.com/schedules/.
Typically, US medical schools allot between four and eight weeks for
dedicated Step 1 preparation. The time you dedicate to exam preparation
will depend on your confidence in comfortably achieving a passing score
as well as your success in preparing yourself during the first two years of
medical school. Some students reserve about a week at the end of their
study period for final review; others save just a few days. When you have
scheduled your exam date, do your best to adhere to it.

Make your schedule realistic, and set achievable goals. Many students make
the mistake of studying at a level of detail that requires too much time for a
comprehensive review—reading Gray’s Anatomy in a couple of days is not a
realistic goal! Have one catch-up day per week of studying. No matter how
well you stick to your schedule, unexpected events happen. But don’t let
yourself procrastinate because you have catch-up days; stick to your schedule
as closely as possible and revise it regularly on the basis of your actual
progress. Be careful not to lose focus. Beware of feelings of inadequacy when
comparing study schedules and progress with your peers. Avoid others who
stress you out. Focus on a few top-rated resources that suit your learning
style—not on some obscure books your friends may pass down to you.
Accept the fact that you cannot learn it all.
You will need time for uninterrupted and focused study. Plan your ` Avoid burnout. Maintain proper diet, exercise,
personal affairs to minimize crisis situations near the date of the test. Allot and sleep habits.
an adequate number of breaks in your study schedule to avoid burnout.
Maintain a healthy lifestyle with proper diet, exercise, and sleep.
Another important aspect of your preparation is your studying environment.

Study where you have always been comfortable studying. Be sure to
include everything you need close by (review books, notes, coffee, snacks,
etc). If you’re the kind of person who cannot study alone, form a study group
with other students taking the exam. The main point here is to create a
comfortable environment with minimal distractions.
Year(s) Prior
The knowledge you gained during your first two years of medical school and ` Buy review resources early (first year) and use
even during your undergraduate years should provide the groundwork on while studying for courses.
which to base your test preparation. Student scores on NBME subject tests
(commonly known as “shelf exams”) have been shown to be highly correlated
with subsequent Step 1 performance.16 Moreover, undergraduate science
GPAs as well as MCAT scores are strong predictors of performance on the
Step 1 exam.17
We also recommend that you buy highly rated review books early in your first
year of medical school and use them as you study throughout the two years.
When Step 1 comes along, these books will be familiar and personalized to the
way in which you learn. It is risky and intimidating to use unfamiliar review
books in the final two or three weeks preceding the exam. Some students find
it helpful to personalize and annotate First Aid throughout the curriculum.
Months Prior
Review test dates and the application procedure. Testing for the USMLE
Step 1 is done on a year-round basis. If you have disabilities or special
circumstances, contact the NBME as early as possible to discuss test
accommodations (see the Section I Supplement at www.firstaidteam.com/
bonus).

` Simulate the USMLE Step 1 under “real” Use this time to finalize your ideal schedule. Consider upcoming breaks
conditions before beginning your studies. and whether you want to relax or study. Work backward from your test date
to make sure you finish at least one question bank. Also add time to redo
missed or flagged questions (which may be half the bank). This is the time to
build a structured plan with enough flexibility for the realities of life.
Begin doing blocks of questions from reputable question banks under “real”
conditions. Don’t use tutor mode until you’re sure you can finish blocks
in the allotted time. It is important to continue balancing success in your
normal studies with the Step 1 test preparation process.
Weeks Prior (Dedicated Preparation)
` In the final two weeks, focus on review,

Your dedicated prep time may be one week or two months. You should have
practice questions, and endurance. Stay
a working plan as you go into this period. Finish your schoolwork strong, take
confident!
a day off, and then get to work. Start by simulating a full-length USMLE
Step 1 if you haven’t yet done so. Consider doing one NBME CBSSA and
the free questions from the NBME website. Alternatively, you could choose 7
blocks of randomized questions from a commercial question bank. Make sure
you get feedback on your strengths and weaknesses and adjust your studying
accordingly. Many students study from review sources or comprehensive
programs for part of the day, then do question blocks. Also, keep in mind that
reviewing a question block can take upward of two hours. Feedback from
CBSSA exams and question banks will help you focus on your weaknesses.
One Week Prior
` One week before the test: Make sure you have your CIN (found on your scheduling permit) as
Sleep according to the same schedule you’ll well as other items necessary for the day of the examination, including
use on test day a current driver’s license or another form of photo ID with your signature
Review the CBT tutorial one last time (make sure the name on your ID exactly matches that on your scheduling
Call Prometric to confirm test date and time permit). Confirm the Prometric testing center location and test time. Work
out how you will get to the testing center and what parking, traffic, and
public transportation problems you might encounter. Exchange cell phone
numbers with other students taking the test on the same day in case of
emergencies. Check www.prometric.com/closures for test site closures due
to unforeseen events. Determine what you will do for lunch. Make sure you
have everything you need to ensure that you will be comfortable and alert at
the test site. It may be beneficial to adjust your schedule to start waking up
at the same time that you will on your test day. And of course, make sure to
maintain a healthy lifestyle and get enough sleep.
One Day Prior
Try your best to relax and rest the night before the test. Double-check your
admissions and test-taking materials as well as the comfort measures discussed
earlier so that you will not have to deal with such details on the morning of
the exam. At this point it will be more effective to review short-term memory

material that you’re already familiar with than to try to learn new material.
The Rapid Review section at the end of this book is high yield for last-minute
studying. Remember that regardless of how hard you have studied, you cannot
(and need not!) know everything. There will be things on the exam that you have
never even seen before, so do not panic. Do not underestimate your abilities.
Many students report difficulty sleeping the night prior to the exam. This is
often exacerbated by going to bed much earlier than usual. Do whatever it
takes to ensure a good night’s sleep (eg, massage, exercise, warm milk, no
screens at night). Do not change your daily routine prior to the exam. Exam
day is not the day for a caffeine-withdrawal headache.
Morning of the Exam
On the morning of the Step 1 exam, wake up at your regular time and ` No notes, books, calculators, pagers, cell
eat a normal breakfast. If you think it will help you, have a close friend phones, recording devices, or watches of any
or family member check to make sure you get out of bed. Make sure you kind are allowed in the testing area, but they
have your scheduling permit admission ticket, test-taking materials, and are allowed in lockers and may be accessed
comfort measures as discussed earlier. Wear loose, comfortable clothing. during authorized breaks.
Limiting the number of pockets in your outfit may save time during security
screening. Plan for a variable temperature in the testing center. Arrive at
the test site 30 minutes before the time designated on the admission ticket; ` Arrive at the testing center 30 minutes before
however, do not come too early, as doing so may intensify your anxiety. your scheduled exam time. If you arrive
When you arrive at the test site, the proctor should give you a USMLE more than half an hour late, you will not be
information sheet that will explain critical factors such as the proper use of allowed to take the test.
break time. Seating may be assigned, but ask to be reseated if necessary; you
need to be seated in an area that will allow you to remain comfortable and
to concentrate. Get to know your testing station, especially if you have never
been in a Prometric testing center before. Listen to your proctors regarding
any changes in instructions or testing procedures that may apply to your test
site.
If you are experiencing symptoms of illness on the day of your exam, we

strongly recommend you reschedule. If you become ill or show signs of
illness (eg, persistent cough) during the exam, the test center may prohibit
you from completing the exam due to health and safety risks for test center
staff and other examinees.
Finally, remember that it is natural (and even beneficial) to be a little

nervous. Focus on being mentally clear and alert. Avoid panic. When you
are asked to begin the exam, take a deep breath, focus on the screen, and
then begin. Keep an eye on the timer. Take advantage of breaks between
blocks to stretch, maybe do some jumping jacks, and relax for a moment
with deep breathing or stretching.
After the Test
After you have completed the exam, be sure to have fun and relax regardless
of how you may feel. Taking the test is an achievement in itself. Remember,

you are much more likely to have passed than not. Enjoy the free time
you have before your clerkships. Expect to experience some “reentry”
phenomena as you try to regain a real life. Once you have recovered
sufficiently from the test (or from partying), we invite you to send us your
feedback, corrections, and suggestions for entries, facts, mnemonics,
strategies, resource ratings, and the like (see p. xvii, How to Contribute).
Sharing your experience will benefit fellow medical students.
STUDY MATERIALS
`
Quality Considerations
Although an ever-increasing number of review books and software are now

available on the market, the quality of such material is highly variable. Some
common problems are as follows:
Certain review books are too detailed to allow for review in a reasonable
amount of time or cover subtopics that are not emphasized on the exam.
Many sample question books were originally written years ago and have
not been adequately updated to reflect recent trends.
Some question banks test to a level of detail that you will not find on the
exam.
Review Books
` If a given review book is not working for you, In selecting review books, be sure to weigh different opinions against each
stop using it no matter how highly rated it other, read the reviews and ratings in Section IV of this guide, examine the
may be or how much it costs. books closely in the bookstore, and choose carefully. You are investing not
only money but also your limited study time. Do not worry about finding
the “perfect” book, as many subjects simply do not have one, and different
students prefer different formats. Supplement your chosen books with personal
notes from other sources, including what you learn from question banks.
` Charts and diagrams may be the best There are two types of review books: those that are stand-alone titles and
approach for physiology and biochemistry, those that are part of a series. Books in a series generally have the same style,
whereas tables and outlines may be and you must decide if that style works for you. However, a given style is not
preferable for microbiology. optimal for every subject.
You should also find out which books are up to date. Some recent editions
reflect major improvements, whereas others contain only cursory changes.
Take into consideration how a book reflects the format of the USMLE Step 1.
Apps
With the explosion of smartphones and tablets, apps are an increasingly

popular way to review for the Step 1 exam. The majority of apps are
compatible with both iOS and Android. Many popular Step 1 review
resources (eg, UWorld, USMLE-Rx) have apps that are compatible with

their software. Many popular web references (eg, UpToDate) also now offer
app versions. All of these apps offer flexibility, allowing you to study while
away from a computer (eg, while traveling).
Practice Tests
Taking practice tests provides valuable information about potential strengths

` Most practice exams are shorter and less
and weaknesses in your fund of knowledge and test-taking skills. Some
clinical than the real thing.
students use practice examinations simply as a means of breaking up the
monotony of studying and adding variety to their study schedule, whereas
other students rely almost solely on practice. You should also subscribe to
one or more high-quality question banks.
Additionally, some students preparing for the Step 1 exam have started to
incorporate case-based books intended primarily for clinical students on the
wards or studying for the Step 2 CK exam. First Aid Cases for the USMLE
Step 1 aims to directly address this need.
After taking a practice test, spend time on each question and each answer
choice whether you were right or wrong. There are important teaching
points in each explanation. Knowing why a wrong answer choice is incorrect
is just as important as knowing why the right answer is correct. Do not panic ` Use practice tests to identify concepts and
if your practice scores are low as many questions try to trick or distract you to areas of weakness, not just facts that you
highlight a certain point. Use the questions you missed or were unsure about missed.
to develop focused plans during your scheduled catch-up time.
Textbooks and Course Syllabi
Limit your use of textbooks and course syllabi for Step 1 review. Many
textbooks are too detailed for high-yield review and include material that
is generally not tested on the USMLE Step 1 (eg, drug dosages, complex
chemical structures). Syllabi, although familiar, are inconsistent across
medical schools and frequently reflect the emphasis of individual faculty,
which often does not correspond to that of the USMLE Step 1. Syllabi also
tend to be less organized than top-rated books and generally contain fewer
diagrams and study questions.
TEST-TAKING STRATEGIES
`
Your test performance will be influenced by both your knowledge and your ` Practice! Develop your test-taking skills and
test-taking skills. You can strengthen your performance by considering each strategies well before the test date.
of these factors. Test-taking skills and strategies should be developed and
perfected well in advance of the test date so that you can concentrate on the
test itself. We suggest that you try the following strategies to see if they might
work for you.

Pacing
You have seven hours to complete up to 280 questions. Note that each one-
hour block contains up to 40 questions. This works out to approximately
90 seconds per question. We recommend following the “1 minute rule” to pace
yourself. Spend no more than 1 minute on each question. If you are still unsure
about the answer after this time, mark the question, make an educated guess,
and move on. Following this rule, you should have approximately 20 minutes
left after all questions are answered, which you can use to revisit all of your
marked questions. Remember that some questions may be experimental
and do not count for points (and reassure yourself that these experimental
questions are the ones that are stumping you). In the past, pacing errors have
` Time management is an important skill for
been detrimental to the performance of even highly prepared examinees. The
exam success.
bottom line is to keep one eye on the clock at all times!
Dealing with Each Question
There are several established techniques for efficiently approaching

multiple choice questions; find what works for you. One technique begins
with identifying each question as easy, workable, or impossible. Your goal
should be to answer all easy questions, resolve all workable questions in a
reasonable amount of time, and make quick and intelligent guesses on all
impossible questions. Most students read the stem, think of the answer, and
turn immediately to the choices. A second technique is to first skim the
answer choices to get a context, then read the last sentence of the question
(the lead-in), and then read through the passage quickly, extracting only
information relevant to answering the question. This can be particularly
helpful for questions with long clinical vignettes. Try a variety of techniques
on practice exams and see what works best for you. If you get overwhelmed,
remember that a 30-second time out to refocus may get you back on track.
Guessing
There is no penalty for wrong answers. Thus no test block should be left
with unanswered questions. If you don’t know the answer, first eliminate
incorrect choices, then guess among the remaining options. Note that
dozens of questions are unscored experimental questions meant to obtain
statistics for future exams. Therefore, some questions may seem unusual
or unreasonably difficult simply because they are part of the development
process for future exams.
Changing Your Answer
The conventional wisdom is not to second-guess your initial answers.

However, studies have consistently shown that test takers are more likely
to change from a wrong answer to the correct answer than the other way
around. Many question banks tell you how many questions you changed
from right to wrong, wrong to wrong, and wrong to right. Use this feedback

to judge how good a second-guesser you are. If you have extra time, reread ` Go with your first hunch, unless you are
the question stem and make sure you didn’t misinterpret the question. certain that you are a good second-guesser.
CLINICAL VIGNETTE STRATEGIES

`
In recent years, the USMLE Step 1 has become increasingly clinically ` Be prepared to read fast and think on your
oriented. This change mirrors the trend in medical education toward feet!
introducing students to clinical problem solving during the basic science
years. The increasing clinical emphasis on Step 1 may be challenging to
those students who attend schools with a more traditional curriculum.
What Is a Clinical Vignette?
A clinical vignette is a short (usually paragraph-long) description of a patient,

including demographics, presenting symptoms, signs, and other information
concerning the patient. Sometimes this paragraph is followed by a brief
listing of important physical findings and/or laboratory results. The task of
assimilating all this information and answering the associated question in the ` Practice questions that include case histories
span of one minute can be intimidating. So be prepared to read quickly and or descriptive vignettes are critical for Step 1
think on your feet. Remember that the question is often indirectly asking preparation.
something you already know.
A pseudovignette is a question that includes a description of a case similar to

that of a clinical vignette, but it ends with a declarative recall question; thus
the material presented in the pseudovignette is not necessary to answer the
question. Question writers strive to avoid pseudovignettes on the USMLE
Step 1. Be prepared to tackle each vignette as if the information presented is
important to answer the associated question correctly.
Strategy
Remember that Step 1 vignettes usually describe diseases or disorders in

their most classic presentation. So look for cardinal signs (eg, malar rash for
lupus or nuchal rigidity for meningitis) in the narrative history. Be aware that
the question will contain classic signs and symptoms instead of buzzwords. ` Step 1 vignettes usually describe diseases or
Sometimes the data from labs and the physical exam will help you confirm disorders in their most classic presentation.
or reject possible diagnoses, thereby helping you rule answer choices in or
out. In some cases, they will be a dead giveaway for the diagnosis.
Making a diagnosis from the history and data is often not the final answer. Not
infrequently, the diagnosis is divulged at the end of the vignette, after you have
just struggled through the narrative to come up with a diagnosis of your own.
The question might then ask about a related aspect of the diagnosed disease.
Consider skimming the answer choices and lead-in before diving into a long
stem. However, be careful with skimming the answer choices; going too fast
may warp your perception of what the vignette is asking.

IF YOU THINK YOU FAILED

`
After taking the test, it is normal for many examinees to feel unsure about
their performance, despite the majority of them achieving a passing score.
Historical pass data is in Table 2. If you remain quite concerned, it may
be wise to prepare a course of action should you need to retest. There are
several sensible steps you can take to plan for the future in the event that
you do not achieve a passing score. First, save and organize all your study
materials, including review books, practice tests, and notes. Familiarize
yourself with the reapplication procedures for Step 1, including application
deadlines and upcoming test dates.
Make sure you know both your school’s and the NBME’s policies regarding
retakes. The total number of attempts an examinee may take per Step
` If you pass Step 1, you are not allowed to examination is four.18 You make take Step 1 no more than three times within
retake the exam. a 12-month period. Your fourth attempt must be at least 12 months after
your first attempt at that exam, and at least 6 months after your most recent
attempt at that exam.
If you failed, the performance profiles on the back of the USMLE Step 1
score report provide valuable feedback concerning your relative strengths
and weaknesses. Study these profiles closely. Set up a study timeline to
strengthen gaps in your knowledge as well as to maintain and improve what
you already know. Do not neglect high-yield subjects. It is normal to feel
somewhat anxious about retaking the test, but if anxiety becomes a problem,
seek appropriate counseling.
TESTING AGENCIES
`
National Board of Medical Examiners (NBME) / USMLE Secretariat

Department of Licensing Examination Services
3750 Market Street
Philadelphia, PA 19104-3102
(215) 590-9500 (operator) or
(215) 590-9700 (automated information line)
Email: webmail@nbme.org
www.nbme.org
Educational Commission for Foreign Medical Graduates (ECFMG)

3624 Market Street
Philadelphia, PA 19104-2685
(215) 386-5900
Email: info@ecfmg.org
www.ecfmg.org

REFERENCES
`
1. United States Medical Licensing Examination. Available from: https://
www.usmle.org/prepare-your-exam/step-1-materials/step-1-content-outline-
and-specifications. Accessed October 2022.
2. United States Medical Licensing Examination. Performance Data. Available
from: https://www.usmle.org/performance-data. Accessed October 2022.
3. Prober CG, Kolars JC, First LR, et al. A plea to reassess the role of United
States Medical Licensing Examination Step 1 scores in residency selection.
Acad Med. 2016;91(1):12–15.
4. Roediger HL, Butler AC. The critical role of retrieval practice in long-term
retention. Trends Cogn Sci. 2011;15(1):20–27.
5. Dunlosky J, Rawson KA, Marsh EJ, et al. Improving students’ learning
with effective learning techniques: promising directions from cognitive and
educational psychology. Psychol Sci Publ Int. 2013;14(1):4–58.
6. Larsen DP, Butler AC, Lawson AL, et al. The importance of seeing the
patient: test-enhanced learning with standardized patients and written
tests improves clinical application of knowledge. Adv Health Sci Educ.
2013;18(3):409–425.
7. Panus PC, Stewart DW, Hagemeier NE, et al. A subgroup analysis of the
impact of self-testing frequency on examination scores in a pathophysiology
course. Am J Pharm Educ. 2014;78(9):165.
8. Deng F, Gluckstein JA, Larsen DP. Student-directed retrieval practice is
a predictor of medical licensing examination performance. Perspect Med
Educ. 2015;4(6):308–313.
9. McAndrew M, Morrow CS, Atiyeh L, et al. Dental student study strategies:
are self-testing and scheduling related to academic performance? J Dent
Educ. 2016;80(5):542–552.
10. Augustin M. How to learn effectively in medical school: test yourself, learn
actively, and repeat in intervals. Yale J Biol Med. 2014;87(2):207–212.
11. Bellezza FS. Mnemonic devices: classification, characteristics, and criteria.
Rev Educ Res. 1981;51(2):247–275.
12. Dyer J-O, Hudon A, Montpetit-Tourangeau K, et al. Example-based
learning: comparing the effects of additionally providing three different
integrative learning activities on physiotherapy intervention knowledge.
BMC Med Educ. 2015;15:37.
13. Chamberland M, Mamede S, St-Onge C, et al. Self-explanation in learning
clinical reasoning: the added value of examples and prompts. Med Educ.
2015;49(2):193–202.
14. Nesbit JC, Adesope OO. Learning with concept and knowledge maps: a
meta-analysis. Rev Educ Res. 2006;76(3):413–448.
15. Pohl CA, Robeson MR, Hojat M, et al. Sooner or later? USMLE Step 1
performance and test administration date at the end of the second year. Acad
Med. 2002;77(10):S17–S19.
16. Holtman MC, Swanson DB, Ripkey DR, et al. Using basic science
subject tests to identify students at risk for failing Step 1. Acad Med.
2001;76(10):S48–S51.
17. Basco WT, Way DP, Gilbert GE, et al. Undergraduate institutional
MCAT scores as predictors of USMLE Step 1 performance. Acad Med.
2002;77(10):S13–S16.
18. United States Medical Licensing Examination. What are the rules regarding
retakes? Available from: https://www.usmle.org/common-questions/general.
Accessed October 2022.

HIGH-YIELD PRINCIPLES IN
Biochemistry
“The nitrogen in our DNA, the calcium in our teeth, the iron in our blood, ` Molecular 32
the carbon in our apple pies were made in the interiors of collapsing stars.
We are made of starstuff.” ` Cellular 44
—Carl Sagan
` Laboratory Techniques 50
“Biochemistry is the study of carbon compounds that crawl.”
—Mike Adams ` Genetics 54
“The power to control our species’ genetic future is awesome and ` Nutrition 63
terrifying.”
—A Crack in Creation ` Metabolism 71
“Nothing in this world is to be feared, it is only to be understood.”

—Marie Curie
This high-yield material includes molecular biology, genetics, cell

biology, and principles of metabolism (especially vitamins, cofactors,
minerals, and single-enzyme-deficiency diseases). When studying
metabolic pathways, emphasize important regulatory steps and enzyme
deficiencies that result in disease, as well as reactions targeted by
pharmacologic interventions. For example, understanding the defect
in Lesch-Nyhan syndrome and its clinical consequences is higher yield
than memorizing every intermediate in the purine salvage pathway.
Do not spend time learning details of organic chemistry, mechanisms, or

physical chemistry. Detailed chemical structures are infrequently tested;
however, many structures have been included here to help students
learn reactions and the important enzymes involved. Familiarity with
the biochemical techniques that have medical relevance—such as
ELISA, immunoelectrophoresis, Southern blotting, and PCR—is
useful. Review the related biochemistry when studying pharmacology or
genetic diseases as a way to reinforce and integrate the material.
31
FAS1_2023_01-Biochem.indd 31 11/17/22 7:11 PM

32 SEC TION II Biochemistry 
BIOCHEMISTRY—Molecular
BIOCHEMISTRY—MOLECULAR
`
Chromatin structure DNA exists in the condensed, chromatin form to DNA has ⊝ charge from phosphate groups.
fit into the nucleus. DNA loops twice around a Histones are large and have ⊕ charge from
histone octamer to form a nucleosome (“beads lysine and arginine.
on a string”). H1 binds to the nucleosome In mitosis, DNA condenses to form
and to “linker DNA,” thereby stabilizing the chromosomes. DNA and histone synthesis
chromatin fiber. occurs during S phase.
Mitochondria have their own DNA, which is
circular and does not utilize histones.
DNA doub
le-hel
ix
H1 histone
(linker)
DNA
Euchromatin
Nucleosome
(H2A, H2B,
H3, H4) 2 Supercoiled
structure
Heterochromatin
Metaphase
chromosome
Heterochromatin Condensed, appears darker on EM (labeled H Heterochromatin = highly condensed.

A
in A ; Nu, nucleolus). Sterically inaccessible, Barr bodies (inactive X chromosomes) may be
E thus transcriptionally inactive. methylation, visible on the periphery of nucleus.
H acetylation.
Nu
Euchromatin Less condensed, appears lighter on EM (labeled Eu = true, “truly transcribed.”

E in A ). Transcriptionally active, sterically Euchromatin is expressed.
accessible.
DNA methylation Changes the expression of a DNA segment DNA is methylated in imprinting.
without changing the sequence. Involved with Methylation within gene promoter (CpG islands)
aging, carcinogenesis, genomic imprinting, typically represses (silences) gene transcription.
transposable element repression, and X CpG methylation makes DNA mute.
chromosome inactivation (lyonization). Dysregulated DNA methylation is implicated in
Fragile X syndrome.
Histone methylation Usually causes reversible transcriptional Histone methylation mostly makes DNA mute.
suppression, but can also cause activation Lysine and arginine residues of histones can be
depending on location of methyl groups. methylated.
Histone acetylation Removal of histone’s ⊕ charge relaxed DNA Thyroid hormone synthesis is altered by
coiling transcription. acetylation of thyroid hormone receptor.
Histone acetylation makes DNA active.
Histone deacetylation Removal of acetyl groups tightened DNA Histone deacetylation may be responsible for
coiling transcription. altered gene expression in Huntington disease.
Histone deacetylation deactivates DNA.

Biochemistry 
BIOCHEMISTRY—Molecular SEC TION II 33
Nucleotides Nucleoside = base + (deoxy)ribose (sugar).

Nucleotide = base + (deoxy)ribose + phosphate; 5′ end of incoming nucleotide bears the
linked by 3′-5′ phosphodiester bond. triphosphate (energy source for the bond).
α-Phosphate is target of 3′ hydroxyl attack.
Purines (A,G)—2 rings. Pure As Gold.

Pyrimidines (C,U,T)—1 ring. CUT the pyramid.
Thymine has a methyl.
Deamination reactions: C-G bond (3 H bonds) stronger than A-T bond
Cytosine uracil (2 H bonds). C-G content melting
Adenine hypoxanthine temperature of DNA. “C-G bonds are like
Guanine xanthine Crazy Glue.”
5-methylcytosine thymine
Amino acids necessary for purine synthesis (cats
Uracil found in RNA; thymine in DNA. purr until they GAG):
Methylation of uracil makes thymine. Glycine
Aspartate
Glutamine
Purine (A, G) Pyrimidine (C, U, T)
CO2 Carbamoyl Aspartate

Glycine phosphate
C N C
Aspartate N C N C
C THF
THF C C C C
N N N
Glutamine

De novo pyrimidine Various immunosuppressive, antineoplastic, and antibiotic drugs function by interfering with
and purine synthesis nucleotide synthesis:
Pyrimidine base production Purine base production or

Pyrimidine synthesis:
(requires aspartate) Ribose 5-P reuse from salvage pathway Leflunomide: inhibits dihydroorotate
Glutamine + CO₂
(de novo requires aspartate, dehydrogenase
glycine, glutamine, and THF)
5-fluorouracil (5-FU) and its prodrug
2 ATP CPS2 (carbamoyl
phosphate capecitabine: form 5-F-dUMP, which inhibits
2 ADP + Pi + PRPP (phosphoribosyl
Glutamate
synthetase II)
pyrophosphate) synthetase thymidylate synthase ( dTMP)
Purine synthesis:
Carbamoyl
phosphate 6-mercaptopurine (6-MP) and its prodrug
Aspartate azathioprine: inhibit de novo purine synthesis
Leflunomide
6-MP, MTX, azathioprine (guanine phosphoribosyltransferase);
PRPP
Orotic azathioprine is metabolized via purine
acid
degradation pathway and can lead to
Impaired in UMP Mycophenolate, immunosuppression when administered with
orotic aciduria IMP ribavirin
UDP xanthine oxidase inhibitor
ctas ide
reduucleot
Hydroxyurea AMP GMP Mycophenolate and ribavirin: inhibit inosine

e
n
monophosphate dehydrogenase
Ribo
dUDP CTP
Purine and pyrimidine synthesis:
Hydroxyurea: inhibits ribonucleotide
N5N10- dUMP
reductase
Thymidylate
methylene THF
synthase
5-FU Methotrexate (MTX), trimethoprim (TMP),

THF
DHF and pyrimethamine: inhibit dihydrofolate
Dihydrofolate
reductase dTMP reductase ( deoxythymidine monophosphate
[dTMP]) in humans (methotrexate),
MTX, TMP,
pyrimethamine bacteria (trimethoprim), and protozoa
(pyrimethamine)
CPS1 = m1tochondria, urea cycle, found in liver

CPS2 = cytwosol, pyrimidine synthesis, found in
most cells

Biochemistry 
Purine salvage deficiencies
Nucleic acids
Catabolism (DNA and RNA) Nucleic acids Ribose 5-phosphate Nucleic acids
PRPP synthetase De novo synthesis
Salvage
Nucleotides GMP IMP AMP
Cladribine, pentostatin
Lesch-Nyhan
syndrome
ADA
HGPRT APRT
Nucleosides Guanosine Inosine Adenosine
SCID
PRPP
Free bases Guanine PRPP Hypoxanthine Adenine
XO
Allopurinol
Xanthine
Febuxostat Degradation and salvage
XO
Uric acid
Urate oxidase (rasburicase)a
Allantoin Excretion
Absent in humans.
a
ADA, adenosine deaminase; APRT, adenine phosphoribosyltransferase; HGPRT, hypoxanthine guanine phosphoribosyltransferase, XO, xanthine
oxidase; SCID, severe combined immune deficiency (autosomal recessive inheritance)
Adenosine deaminase ADA is required for degradation of adenosine One of the major causes of autosomal recessive
deficiency and deoxyadenosine. ADA dATP SCID.
ribonucleotide reductase activity
DNA precursors in cells lymphocytes.
Lesch-Nyhan Defective purine salvage. Absent HGPRT HGPRT:
syndrome GMP (from guanine) and IMP (from Hyperuricemia
hypoxanthine) formation. Compensatory in Gout
purine synthesis ( PRPP amidotransferase Pissed off (aggression, self-mutilation)
activity) excess uric acid production. Red/orange crystals in urine
X-linked recessive. Tense muscles (dystonia)
Findings: intellectual disability, self-mutilation, Treatment: allopurinol, febuxostat.
aggression, hyperuricemia (red/orange “sand”
[sodium urate crystals] in diaper), gout,
dystonia, macrocytosis.
Genetic code features

Unambiguous Each codon specifies only 1 amino acid.
Degenerate/ Most amino acids are coded by multiple codons. Exceptions: methionine (AUG) and tryptophan
redundant Wobble hypothesis—first 2 nucleotides of (UGG) encoded by only 1 codon.
codon are essential for anticodon recognition
while the 3rd nucleotide can differ (“wobble”).
Commaless, Read from a fixed starting point as a continuous Exceptions: some viruses.
nonoverlapping sequence of bases.
Universal Genetic code is conserved throughout Exception in humans: mitochondria.
evolution.

DNA replication Occurs in 5′ 3′ direction (“5ynth3sis”) in continuous and discontinuous (Okazaki fragment) fashion.
Semiconservative. More complex in eukaryotes than in prokaryotes, but shares analogous enzymes.
Origin of Particular consensus sequence in genome AT-rich sequences (eg, TATA box regions) are
replication A where DNA replication begins. May be single found in promoters (often upstream) and
(prokaryotes) or multiple (eukaryotes). origins of replication (ori).
Replication fork B Y-shaped region along DNA template where
leading and lagging strands are synthesized.
Helicase C Unwinds DNA template at replication fork. Helicase halves DNA.
Deficient in Bloom syndrome (BLM gene
mutation).
Single-stranded Prevent strands from reannealing or degradation
binding proteins D by nucleases.
DNA Creates a single- (topoisomerase I) or double- In eukaryotes: irinotecan/topotecan inhibit
topoisomerases E (topoisomerase II) stranded break in the helix topoisomerase (TOP) I, etoposide/teniposide
to add or remove supercoils (as needed due to inhibit TOP II.
underwinding or overwinding of DNA). In prokaryotes: fluoroquinolones inhibit TOP II
(DNA gyrase) and TOP IV.
Primase F Makes RNA primer for DNA polymerase III to
initiate replication.
DNA polymerase III G Prokaryotes only. Elongates leading strand DNA polymerase III has 5′ 3′ synthesis and
by adding deoxynucleotides to the 3′ end. proofreads with 3′ 5′ exonuclease.
Elongates lagging strand until it reaches Drugs blocking DNA replication often have a
primer of preceding fragment. modified 3′ OH, thereby preventing addition of
the next nucleotide (“chain termination”).
DNA polymerase I H Prokaryotes only. Degrades RNA primer; Same functions as DNA polymerase III, also
replaces it with DNA. excises RNA primer with 5′ 3′ exonuclease.
DNA ligase I Catalyzes the formation of a phosphodiester Joins Okazaki fragments.
bond within a strand of double-stranded DNA. Ligase links DNA.
Telomerase Eukaryotes only. A reverse transcriptase (RNA- Upregulated in progenitor cells and also often in
dependent DNA polymerase) that adds DNA cancer; downregulated in aging and progeria.
(TTAGGG) to 3′ ends of chromosomes to avoid Telomerase TAGs for Greatness and Glory.
loss of genetic material with every duplication.
3'
E
Topoisomerase 5'
C A
Helicase Origin of replication
Leading strand
B G
DNA polymerase
Replication fork Lagging strand 3'
Okazaki fragment 5'
D
A
Area of interest Single-stranded RNA primer
Origin of replication binding protein
Leading strand Lagging strand I
F DNA ligase
Fork Fork Primase
movement movement
Lagging strand Leading strand H

DNA polymerase I

Biochemistry 
DNA repair
Double strand
Nonhomologous end Brings together 2 ends of DNA fragments to 5´
Double strand break
3´ 5´
Double strand break
joining repair double-stranded breaks. 3´ 5´ 3´

5´
3´
Homology not required. Part of the DNA may be
lost or translocated. Nonhomologous end joining
May be dysfunctional in ataxia telangiectasia.
Homologous Requires 2 homologous DNA duplexes. DoubleAstrand break Double strand break
5´ 3´ 5´ 3´
recombination strand from damaged dsDNA 3´ is repaired 5´ 3´
5´
5´
3´
using a complementary strand from intact 3´ 5´ Homologous recombination
homologous dsDNA as a template.
Nonhomologous end joining
Defective in breast/ovarian cancers with BRCA1
or BRCA2 mutations and in Fanconi anemia.
Restores duplexes accurately without loss of
nucleotides. Homologous recombination
Single strand
Nucleotide excision Specific endonucleases remove the Occurs in G1 phase of cell cycle.
repair oligonucleotides containing damaged bases; Defective in xeroderma pigmentosum
DNA polymerase and ligase fill and reseal the (inability to repair DNA pyrimidine dimers
gap, respectively. Repairs bulky helix-distorting caused by UV exposure). Presents with dry
lesions (eg, pyrimidine dimers). skin, photosensitivity, skin cancer.
Base excision repair Base-specific Glycosylase removes altered base Occurs throughout cell cycle.
and creates AP site (apurinic/apyrimidinic). Important in repair of spontaneous/toxic
One or more nucleotides are removed by deamination.
AP-Endonuclease, which cleaves 5′ end. AP- “GEL Please.”
Lyase cleaves 3′ end. DNA Polymerase-β fills
the gap and DNA ligase seals it.
Mismatch repair Mismatched nucleotides in newly synthesized Occurs predominantly in S phase of cell cycle.
strand are removed and gap is filled and Defective in Lynch syndrome (hereditary
resealed. nonpolyposis colorectal cancer [HNPCC]).
UV exposure
Pyrimidine dimer Deaminated C
T T
U G
A A G A
AP U
site
T T Endonucleases remove Glycosylase removes base Mismatched segment
G
damaged segment G removed
A A A
Endonuclease and lyase
remove backbone segment
G
Newly replaced segment
T T U T
A A G A
Nucelotide excision repair Base excision repair Mismatch repair
A B C

Mutations in DNA Degree of change: silent << missense < nonsense < frameshift. Single nucleotide substitutions are
repaired by DNA polymerase and DNA ligase. Types of single nucleotide (point) mutations:
Transition—purine to purine (eg, A to G) or pyrimidine to pyrimidine (eg, C to T).
Transversion—purine to pyrimidine (eg, A to T) or pyrimidine to purine (eg, C to G).
Single nucleotide substitutions
Silent mutation Codes for same (synonymous) amino acid; often involves 3rd position of codon (tRNA wobble).
Missense mutation Results in changed amino acid (called conservative if new amino acid has similar chemical
structure). Examples: sickle cell disease (substitution of glutamic acid with valine).
Nonsense mutation Results in early stop codon (UGA, UAA, UAG). Usually generates nonfunctional protein. Stop the
nonsense!
Other mutations
Frameshift mutation Deletion or insertion of any number of nucleotides not divisible by 3 misreading of all
nucleotides downstream. Protein may be shorter or longer, and its function may be disrupted or
altered. Examples: Duchenne muscular dystrophy, Tay-Sachs disease, cystic fibrosis.
Splice site mutation Retained intron in mRNA protein with impaired or altered function. Examples: rare causes of
cancers, dementia, epilepsy, some types of β-thalassemia, Gaucher disease, Marfan syndrome.
Original Silent Missense Nonsense Frameshift Frameshift
sequence mutation mutation mutation insertion deletion
T G
Coding DNA
5´
GAG GAA GTG TAG GA G GA C 3´
mRNA codon
5´
GAG GAA GUG UAG GAU GAC 3´
Amino acid Glu Glu Val Stop Asp Asp
Altered amino acids
Lac operon Classic example of a genetic response to an environmental change. Glucose is the preferred
metabolic substrate in E coli, but when glucose is absent and lactose is available, the lac operon is
activated to switch to lactose metabolism. Mechanism of shift:
Low glucose adenylate cyclase activity generation of cAMP from ATP activation of
catabolite activator protein (CAP) transcription.
High lactose unbinds repressor protein from repressor/operator site transcription.
Adenylate
CAP cAMP cyclase Glucose
Binds CAP site, ATP

induces transcription
RNA
Lac operon STATE CAP polymerase
Low glucose
Lactose available
Lac genes strongly expressed
DNA Lacl CAP site Promoter Operator LacZ LacY LacA
genes Repressor protein
High glucose
o r, Lactose unavailable
e ra t o n Lac genes not expressed
Binds opnscripti
blocks tra
Low glucose
Repressor Lactose unavailable Lac genes not expressed
protein CAP
High glucose
site P O
Lactose available Very low (basal) expression
Allolactose Inactivated
(inducer) repressor

Biochemistry 
Functional Enhancer/
silencer Promoter 5´ UTR Open reading frame 3´ UTR Silencer
organization of a
eukaryotic gene Exon Intron Exon Intron Exon
DNA 5´ CAAT TATAAA GT AG GT AG AATAAA 3´

(coding strand)
CAAT Box TATA Box
Polyadenylation signal
Transcription start
Transcription
Exon Intron Exon Intron Exon
Pre-mRNA GU AG GU AG AAUAAA
Splicing
5´ cap
Protein coding region
Mature AAUAAA AAAAAA
mRNA
AUG start codon Stop
Poly-A tail
Translation
Protein
Regulation of gene expression

Promoter Site where RNA polymerase II and multiple Promoter mutation commonly results in
other transcription factors bind to DNA dramatic in level of gene transcription.
upstream from gene locus (AT-rich upstream
sequence with TATA and CAAT boxes, which
differ between eukaryotes and prokaryotes).
Promoters increase ori activity.
Enhancer DNA locus where regulatory proteins Enhancers and silencers may be located close to,
(“activators”) bind, increasing expression of a far from, or even within (in an intron) the gene
gene on the same chromosome. whose expression they regulate.
Silencer DNA locus where regulatory proteins
(“repressors”) bind, decreasing expression of a
gene on the same chromosome.
Epigenetics Changes made to gene expression (heritable Primary mechanisms of epigenetic change
mitotically/meiotically) without a change in include DNA methylation, histone
underlying DNA sequence. modification, and noncoding RNA.

RNA processing Initial transcript is called heterogeneous nuclear Poly-A polymerase does not require a template.
(eukaryotes) RNA (hnRNA). hnRNA is then modified and AAUAAA = polyadenylation signal. Mutation
becomes mRNA. in polyadenylation signal early degradation
The following processes occur in the nucleus: prior to translation.
Cap Coding
5'
Capping of 5′ end (addition of Kozak sequence—initiation site in most
Gppp 7-methylguanosine cap; cotranscriptional) eukaryotic mRNA. Facilitates binding of small
3' Polyadenylation of 3′ end (∼200 A’s poly-A subunit of ribosome to mRNA. Mutations
HO-AAAAA
Tail
tail; posttranscriptional) in sequence impairment of initiation of
Splicing out of introns (posttranscriptional) translation protein synthesis.
Capped, tailed, and spliced transcript is called
mRNA.
mRNA is transported out of nucleus to be
translated in cytosol.
mRNA quality control occurs at cytoplasmic
processing bodies (P-bodies), which contain
exonucleases, decapping enzymes, and
microRNAs; mRNAs may be degraded or
stored in P-bodies for future translation.
RNA polymerases
Eukaryotes RNA polymerase I makes rRNA, the most I, II, and III are numbered in the same order
common (rampant) type; present only in that their products are used in protein
nucleolus. synthesis: rRNA, mRNA, then tRNA.
RNA polymerase II makes mRNA (massive), α-amanitin, found in Amanita phalloides (death
microRNA (miRNA), and small nuclear RNA cap mushrooms), inhibits RNA polymerase II.
(snRNA). Causes dysentery and severe hepatotoxicity if
RNA polymerase III makes 5S rRNA, tRNA ingested.
(tiny). Dactinomycin inhibits RNA polymerase in both
No proofreading function, but can initiate prokaryotes and eukaryotes.
chains. RNA polymerase II opens DNA at
promoter site.
Prokaryotes 1 RNA polymerase (multisubunit complex) Rifamycins (rifampin, rifabutin) inhibit DNA-
makes all 3 kinds of RNA. dependent RNA polymerase in prokaryotes.

Biochemistry 
Introns vs exons Exons contain the actual genetic information Introns are intervening sequences and stay
coding for protein or functional RNA. in the nucleus, whereas exons exit and are
Introns do not code for protein, but are expressed.
important in regulation of gene expression. Alternative splicing—can produce a variety
Different exons are frequently combined by of protein products from a single hnRNA
alternative splicing to produce a larger number (heterogenous nuclear RNA) sequence (eg,
of unique proteins. transmembrane vs secreted Ig, tropomyosin
variants in muscle, dopamine receptors in the
brain, host defense evasion by tumor cells).
Exon 1 Exon 2 Exon 3 Exon 4 Exon 5 Exon 6

5′ 3′
DNA 3′ 5′
Transcription
hnRNA 5′ 3′
1 2 3 4 5 6
Splicing Alternative splicing
mRNA 5′ 3′ 5′ 3′ 5′ 3′
1 2 4 5 6 1 3 5 6 1 3 4 5 6
Translation
1 5 1 5 1 5
Proteins 6 6 6
4 4
2 3 3
Splicing of pre-mRNA Part of process by which precursor mRNA (pre-mRNA) is transformed into mature mRNA. Introns
typically begin with GU and end with AG. Alterations in snRNP assembly can cause clinical
disease; eg, in spinal muscular atrophy, snRNP assembly is affected due to SMN protein
congenital degeneration of anterior horns of spinal cord symmetric weakness (hypotonia, or
“floppy baby syndrome”).
snRNPs are snRNA bound to proteins (eg, Smith [Sm]) to form a spliceosome that cleaves pre-
mRNA. Anti-U1 snRNP antibodies are associated with SLE, mixed connective tissue disease,
other rheumatic diseases.
Primary transcript combines with 5′ splice site U1 snRNP Branch point 3′ splice site
small nuclear ribonucleoproteins
U2 snRNP
(snRNPs) and other proteins to
form spliceosome. 5′ O P GU OH A AG P O 3′
Exon 1 Intron Exon 2
Spliceosome
Cleavage at 5′ splice site; lariat-

shaped (loop) intermediate is
generated. UG
P A
OH 3′ AG P O
Exon 1 Exon 2
Mature mRNA
Cleavage at 3′ splice site; lariat
is released to precisely remove
intron and join 2 exons.
P +
Exon 1 Exon 2 UG
P A
AG OH 3′

tRNA
Structure 75–90 nucleotides, 2º structure, cloverleaf form, anticodon end is opposite 3′ aminoacyl end. All
tRNAs, both eukaryotic and prokaryotic, have CCA at 3′ end along with a high percentage of
chemically modified bases. The amino acid is covalently bound to the 3′ end of the tRNA. CCA
Can Carry Amino acids.
T-arm: contains the TΨC (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-
ribosome binding. T-arm Tethers tRNA molecule to ribosome.
D-arm: contains Dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-
tRNA synthetase. D-arm allows Detection of the tRNA by aminoacyl-tRNA synthetase.
Attachment site: 3′-ACC-5′ is the amino acid ACCeptor site.
Charging Aminoacyl-tRNA synthetase (uses ATP; 1 unique enzyme per respective amino acid) and
binding of charged tRNA to the codon are responsible for the accuracy of amino acid selection.
Aminoacyl-tRNA synthetase matches an amino acid to the tRNA by scrutinizing the amino acid
before and after it binds to tRNA. If an incorrect amino acid is attached, the bond is hydrolyzed.
A mischarged tRNA reads the usual codon but inserts the wrong amino acid.
Structure Charging Pairing
(aminoacylation) (codon-anticodon)
Amino acid Amino acid
O O
Attachment site OH 3´ 3´ 3´
A A A
C C C
C C C
5´ 5´ 5´
IF2
T-arm
D-arm ATP AMP + PPi (initiation factor)
D D D
C Ψ T
Aminoacyl-tRNA C Ψ T C Ψ T
D D D
synthetase
Variable arm
Anticodon
loop U A C U A C Anticodon (5´-CAU-3´) U A C
Wobble
position C C C A U G A U A C
mRNA
Codon
(5´-AUG-3´)
Start and stop codons

mRNA start codon AUG. AUG inAUGurates protein synthesis.
Eukaryotes Codes for methionine, which may be removed
before translation is completed.
Prokaryotes Codes for N-formylmethionine (fMet). fMet stimulates neutrophil chemotaxis.
mRNA stop codons UGA, UAA, UAG. UGA = U Go Away.
Recognized by release factors. UA A = U Are Away.
UAG = U Are Gone.

Biochemistry 
Protein synthesis
Initiation 1. Eukaryotic initiation factors (eIFs) identify Eukaryotes: 40S + 60S 80S (even).
the 5′ cap. Prokaryotes: 30S + 50S 70S (prime).
2. eIFs help assemble the 40S ribosomal Synthesis occurs from N-terminus to
subunit with the initiator tRNA. C-terminus.
3. eIFs released when the mRNA and the
ATP—tRNA Activation (charging).
ribosomal 60S subunit assemble with the
GTP—tRNA Gripping and Going places
complex. Requires GTP.
(translocation).
Elongation A minoacyl-tRNA binds to A site (except for
initiator methionine, which binds the P site), Think of “going APE”:
requires an elongation factor and GTP. A site = incoming Aminoacyl-tRNA.
rRNA (“ribozyme”) catalyzes peptide bond P site = accommodates growing Peptide.
formation, transfers growing polypeptide to E site = holds Empty tRNA as it Exits.
amino acid in A site. Elongation factors are targets of bacterial toxins
Ribosome advances 3 nucleotides toward 3′ (eg, Diphtheria, Pseudomonas).
end of mRNA, moving peptidyl tRNA to P
site (translocation). Shine-Dalgarno sequence—ribosomal binding
site in prokaryotic mRNA. Recognized by 16S
Termination Eukaryotic release factors (eRFs) recognize the
RNA in ribosomal subunit. Enables protein
stop codon and halt translation completed
synthesis initiation by aligning ribosome with
polypeptide is released from ribosome.
start codon so that code is read correctly.
Requires GTP.
60/50S
40/30S 80/70S
M
R
M
M M H
Initiator tRNA
U A C
U A C 5´ A U G C A U G A U 3´ U A C G U A
mRNA
E P A
5´ A U G C A U G A U 3´
Initiation E P A
S Ribosome moves left to
right along mRNA
M Elongation M
H
U G A
G U A U A C
U A C Q G U A
Termination
A U G C A U G A U A U G C A U G A U
5´ 3´ 5´ 3´
E P A E P A
Posttranslational modifications
Trimming Removal of N- or C-terminal propeptides from zymogen to generate mature protein (eg,
trypsinogen to trypsin).
Covalent alterations Phosphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitination.
Chaperone protein Intracellular protein involved in facilitating and maintaining protein folding. In yeast, heat
shock proteins (eg, HSP60) are constitutively expressed, but expression may increase with high
temperatures, acidic pH, and hypoxia to prevent protein denaturing/misfolding.

BIOCHEMISTRY—Cellular
BIOCHEMISTRY—CELLULAR
`
Cell cycle phases Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins,
cyclin-dependent kinases (CDKs), and tumor suppressors. M phase (shortest phase of cell cycle)
includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis
(cytoplasm splits in two). G1 is of variable duration.
REGULATION OF CELL CYCLE
Cyclin-dependent Constitutively expressed but inactive when not bound to cyclin.
kinases
Cyclin-CDK complexes Cyclins are phase-specific regulatory proteins that activate CDKs when stimulated by growth
factors. The cyclin-CDK complex can then phosphorylate other proteins (eg, Rb) to coordinate
cell cycle progression. This complex must be activated/inactivated at appropriate times for cell
cycle to progress.
Tumor suppressors p53 p21 induction CDK inhibition Rb hypophosphorylation (activation) G1-S
progression inhibition. Mutations in tumor suppressor genes can result in unrestrained cell
division (eg, Li-Fraumeni syndrome).
Growth factors (eg, insulin, PDGF, EPO, EGF) bind tyrosine kinase receptors to transition the cell
from G1 to S phase.
CELL TYPES
Permanent Remain in G0, regenerate from stem cells. Neurons, skeletal and cardiac muscle, RBCs.
Stable (quiescent) Enter G1 from G0 when stimulated. Hepatocytes, lymphocytes, PCT, periosteal cells.
Labile Never go to G0, divide rapidly with a short G1. Bone marrow, gut epithelium, skin, hair
Most affected by chemotherapy. follicles, germ cells.
Cell cycle arrest

p21 Cyclin
GO
Cyclin
CDK CDK
DNA damage Rb, p53 modulate G1
p21
G1 restriction point
th
ow
Gr
is
M
es
Li-Fraumeni syndrome
kin
to
(loss of function) Cy
Mito
p53
sis
HPV E6
IN TERPH
BCL-2 BCL-XL
Rb P
DNA
P
P
BAX/BAK
AS
Sy n
Rb E2F S
E
t he
is
s
Caspase activation E2F G2

Gene transcription
Apoptosis
(intrinsic pathway)

Biochemistry 
BIOCHEMISTRY—Cellular SEC TION II 45
Rough endoplasmic Site of synthesis of secretory (exported) proteins N-linked glycosylation occurs in the
reticulum and of N-linked oligosaccharide addition to eNdoplasmic reticulum.
lysosomal and other proteins. Mucus-secreting goblet cells of small intestine
Nissl bodies (RER in neurons)—synthesize and antibody-secreting plasma cells are rich in
peptide neurotransmitters for secretion. RER.
Free ribosomes—unattached to any membrane; Proteins within organelles (eg, ER, Golgi bodies,
site of synthesis of cytosolic, peroxisomal, and lysosomes) are formed in RER.
mitochondrial proteins.
Smooth endoplasmic Site of steroid synthesis and detoxification of Hepatocytes and steroid hormone–producing
reticulum drugs and poisons. Lacks surface ribosomes. cells of the adrenal cortex and gonads are rich
Location of glucose-6-phosphatase (last step in in SER.
both glycogenolysis and gluconeogenesis).
Cell trafficking Golgi is distribution center for proteins and lipids from ER to vesicles and plasma membrane.
Posttranslational events in GOlgi include modifying N-oligosaccharides on asparagine, adding
O-oligosaccharides on serine and threonine, and adding mannose-6-phosphate to proteins for
lysosomal and other proteins.
Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to
lysosomes for destruction or back to the membrane/Golgi for further use.
I-cell disease (inclusion cell disease/mucolipidosis type II)—inherited lysosomal storage disorder
(autosomal recessive); defect in N-acetylglucosaminyl-1-phosphotransferase failure of the
Golgi to phosphorylate mannose residues ( mannose-6-phosphate) on glycoproteins enzymes
secreted extracellularly rather than delivered to lysosomes lysosomes deficient in digestive
enzymes buildup of cellular debris in lysosomes (inclusion bodies). Results in coarse facial
features, gingival hyperplasia, corneal clouding, restricted joint movements, claw hand deformities,
kyphoscoliosis, and plasma levels of lysosomal enzymes. Symptoms similar to but more severe
than Hurler syndrome. Often fatal in childhood.
Key: Signal recognition particle (SRP)—abundant,
brane
cytosolic ribonucleoprotein that traffics
mem polypeptide-ribosome complex from the
Clathrin sma
Pla
Secretory cytosol to the RER. Absent or dysfunctional
vesicle
COPI Late Early SRP accumulation of protein in cytosol.
endosome endosome
COPII Vesicular trafficking proteins

Lysosome COPI: Golgi Golgi (retrograde); cis-Golgi
Retrograde trans ER.
Anterograde COPII: ER cis-Golgi (anterograde). “Two
Golgi (COPII) steps forward (anterograde); one
apparatus (COPI) step back (retrograde).”
Clathrin: trans-Golgi lysosomes; plasma
membrane endosomes (receptor-mediated
cis
endocytosis [eg, LDL receptor activity]).
Rough
endoplasmic
reticulum
Nuclear envelope

Peroxisome Membrane-enclosed organelle involved in:

β-oxidation of very-long-chain fatty acids (VLCFA) (strictly peroxisomal process)
α-oxidation of branched-chain fatty acids (strictly peroxisomal process)
Catabolism of amino acids and ethanol
Synthesis of bile acids and plasmalogens (important membrane phospholipid, especially in
white matter of brain)
Zellweger syndrome—autosomal recessive disorder of peroxisome biogenesis due to mutated PEX
genes. Hypotonia, seizures, jaundice, craniofacial dysmorphia, hepatomegaly, early death.
Refsum disease—autosomal recessive disorder of α-oxidation buildup of phytanic acid due
to inability to degrade it. Scaly skin, ataxia, cataracts/night blindness, shortening of 4th toe,
epiphyseal dysplasia. Treatment: diet, plasmapheresis.
Adrenoleukodystrophy—X-linked recessive disorder of β-oxidation due to mutation in ABCD1
gene VLCFA buildup in adrenal glands, white (leuko) matter of brain, testes. Progressive
disease that can lead to adrenal gland crisis, progressive loss of neurologic function, death.
Proteasome Barrel-shaped protein complex that degrades polyubiquitin-tagged proteins. Plays a role in many
cellular processes, including immune response (MHC I–mediated). Defects in ubiquitin-proteasome
system also implicated in diverse human diseases including neurodegenerative diseases.
Cytoskeletal elements A network of protein fibers within the cytoplasm that supports cell structure, cell and organelle
movement, and cell division.
TYPE OF FILAMENT PREDOMINANT FUNCTION EXAMPLES
Microfilaments Muscle contraction, cytokinesis Actin, microvilli.
Intermediate Maintain cell structure Vimentin, desmin, cytokeratin, lamins, glial
filaments fibrillary acidic protein (GFAP), neurofilaments.
Microtubules Movement, cell division Cilia, flagella, mitotic spindle, axonal trafficking,
centrioles.
Microtubule Cylindrical outer structure composed of a Drugs that act on microtubules (microtubules
Positive
helical array of polymerized heterodimers get constructed very terribly):
end (+) of α- and β-tubulin. Each dimer has 2 GTP Mebendazole (antihelminthic)
Heterodimer bound. Incorporated into flagella, cilia, mitotic Griseofulvin (antifungal)
spindles. Also involved in slow axoplasmic Colchicine (antigout)
transport in neurons. Vinca alkaloids (anticancer)
Molecular motor proteins—transport cellular Taxanes (anticancer)
cargo toward opposite ends of microtubule. Negative end near nucleus.
Protofilament Retrograde to microtubule (+ −)—dynein. Positive end points to periphery.
Anterograde to microtubule (− +)—kinesin.
Negative Clostridium tetani toxin, poliovirus, rabies virus, Ready? Attack!
end (–) and herpes simplex virus (HSV) use dynein
for retrograde transport to the neuronal cell
body. HSV reactivation occurs via anterograde
transport from cell body (kinesin mediated).
Slow anterograde transport rate limiting step of
peripheral nerve regeneration after injury.

Biochemistry 
Cilia structure Motile cilia consist of 9 doublet + 2 singlet arrangement of microtubules (axoneme) A .
Basal body (base of cilium below cell membrane) consists of 9 microtubule triplets B with no
central microtubules.
Nonmotile (primary) cilia work as chemical signal sensors and have a role in signal transduction
and cell growth control. Dysgenesis may lead to polycystic kidney disease, mitral valve prolapse,
or retinal degeneration.
Axonemal dynein—ATPase that links peripheral 9 doublets and causes bending of cilium by
differential sliding of doublets.
Gap junctions enable coordinated ciliary movement.
A B
Dynein
arm
Microtubule
A
Microtubule
B
Nexin
Doublets
Triplets
Primary ciliary Autosomal recessive. Dynein arm defect immotile cilia dysfunctional ciliated epithelia. Most
dyskinesia common type is Kartagener syndrome (PCD with situs inversus).
Developmental abnormalities due to impaired migration and orientation (eg, situs inversus A , hearing
A
loss due to dysfunctional eustachian tube cilia); recurrent infections (eg, sinusitis, ear infections,
R L bronchiectasis due to impaired ciliary clearance of debris/pathogens); infertility ( risk of ectopic
pregnancy due to dysfunctional fallopian tube cilia, immotile spermatozoa).
Lab findings: nasal nitric oxide (used as screening test).
Sodium-potassium Na+/K+-ATPase is located in the plasma 2 strikes? K, you’re still in. 3 strikes? Nah, you’re
pump membrane with ATP site on cytosolic side. For out!
each ATP consumed, 2 K+ go in to the cell Digoxin directly inhibits Na+/K+-ATPase
(pump dephosphorylated) and 3 Na+ go out of indirect inhibition of Na+/Ca2+ exchange
the cell (pump phosphorylated). [Ca2+]i cardiac contractility.
Extracellular
3Na+ 2K+
space
Plasma
membrane
P
Cytosol 2K+
3Na+ ATP ADP P

Collagen Most abundant protein in the human body. Type I - Skeleton

Extensively modified by posttranslational Type II - Cartilage
modification. Type III - Arteries
Organizes and strengthens extracellular matrix. Type IV - Basement membrane
Types I to IV are the most common types in SCAB
humans.
Type I Most common (90%)—Bone (made by Type I: bone, tendone.
osteoblasts), Skin, Tendon, dentin, fascia, production in osteogenesis imperfecta type I.
cornea, late wound repair.
Type II Cartilage (including hyaline), vitreous body, Type II: cartwolage.
nucleus pulposus.
Type III Reticulin—skin, blood vessels, uterus, fetal Type III: deficient in vascular type of Ehlers-
tissue, early wound repair. Danlos syndrome (threE D).
Type IV Basement membrane/basal lamina (glomerulus, Type IV: under the floor (basement membrane).
cochlea), lens. Defective in Alport syndrome; targeted by
autoantibodies in Goodpasture syndrome.
Myofibroblasts are responsible for secretion
(proliferative stage) and wound contraction.
Collagen synthesis and structure
Fibroblast Preprocollagen S ynthesis—translation of collagen α

Pro α-chain backbone (Gly-X-Y) chains (preprocollagen)—usually Gly-X-Y
Nucleus Hydroxylation of proline and
(X is often proline or lysine and Y is often
OH
OH lysine (requires vitamin C) hydroxyproline or hydroxylysine). Collagen is
Collagen mRNA Sugar
Glycosylation
1/3 glycine; glycine content of collagen is less
Cytoplasm OH
OH variable than that of lysine and proline.
RER
Hydroxylation—hydroxylation
Triple helix formation
Procollagen (“hydroxCylation”) of specific proline
Golgi and lysine residues. Requires vitamin C;
deficiency scurvy.
Exocytosis
Glycosylation—glycosylation of pro-α-chain
Extracellular
space hydroxylysine residues and formation of
Cleavage of procollagen
C- and N-terminals procollagen via hydrogen and disulfide bonds
Tropocollagen (triple helix of 3 collagen α chains). Problems
forming triple helix osteogenesis imperfecta.
Self assembly into
collagen fibrils Exocytosis—exocytosis of procollagen into
extracellular space.
Proteolytic processing—cleavage of
disulfide-rich terminal regions of procollagen
Formation of cross-links
(stabilized by lysyl oxidase) insoluble tropocollagen.
Assembly and alignment—collagen assembles
Collagen fiber
in fibrils and aligns for cross-linking.
Cross-linking—reinforcement of staggered
tropocollagen molecules by covalent lysine-
hydroxylysine cross-linkage (by copper-
containing lysyl oxidase) to make collagen
fibers. Cross-linking of collagen with age.
Problems with cross-linking Menkes disease.

Biochemistry 
Osteogenesis Genetic bone disorder (brittle bone May be confused with child abuse.
imperfecta disease) caused by a variety of gene defects Treat with bisphosphonates to fracture risk.
A
(most commonly COL1A1 and COL1A2). Patients can’t BITE:
Most common form is autosomal dominant Bones = multiple fractures
with production of otherwise normal type I I (eye) = blue sclerae
collagen (altered triple helix formation). Teeth = dental imperfections
Upper Manifestations include: Ear = hearing loss
extremity Multiple fractures and bone deformities
B
(arrows in A ) after minimal trauma (eg,
during birth)
Blue sclerae B due to the translucent
connective tissue over choroidal veins
Some forms have tooth abnormalities,
including opalescent teeth that wear easily
due to lack of dentin (dentinogenesis
imperfecta)
Conductive hearing loss (abnormal ossicles)
Ehlers-Danlos Faulty collagen synthesis causing A B

syndrome hyperextensible skin A , hypermobile joints B ,
and tendency to bleed (easy bruising).
Multiple types. Inheritance and severity vary.
Can be autosomal dominant or recessive. May
be associated with joint dislocation, berry and
aortic aneurysms, organ rupture.
Hypermobility type (joint instability): most
common type.
Classical type (joint and skin symptoms):
caused by a mutation in type V collagen (eg,
COL5A1, COL5A2).
Vascular type (fragile tissues including vessels
[eg, aorta], muscles, and organs that are prone
to rupture [eg, gravid uterus]): mutations in
type III procollagen (eg, COL3A1).
Can be caused by procollagen peptidase
deficiency.
Menkes disease X-linked recessive connective tissue disease caused by impaired copper absorption and transport
due to defective Menkes protein ATP7A (Absent copper), vs ATP7B in Wilson disease (copper
Buildup). Leads to activity of lysyl oxidase (copper is a necessary cofactor) defective collagen
cross-linking. Results in brittle, “kinky” hair, growth and developmental delay, hypotonia, risk of
cerebral aneurysms.

Biochemistry—Laboratory Techniques
Elastin Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, epiglottis,
ligamenta flava (connect vertebrae relaxed and stretched conformations).
Rich in nonhydroxylated proline, glycine, and lysine residues, vs the hydroxylated residues of
collagen.
Single Tropoelastin with fibrillin scaffolding.
elastin Stretch
Relax Cross-link
Cross-linking occurs extracellularly via lysyl oxidase and gives elastin its elastic properties.
molecule
Broken down by elastase, which is normally inhibited by α1-antitrypsin.
α1-Antitrypsin deficiency results in unopposed elastase activity, which can cause COPD.
Marfan syndrome—autosomal dominant (with variable expression) connective tissue disorder
A
affecting skeleton, heart, and eyes. FBN1 gene mutation on chromosome 15 (fifteen) results in
defective fibrillin-1, a glycoprotein that forms a sheath around elastin and sequesters TGF-β.
Findings: tall with long extremities; chest wall deformity (pectus carinatum [pigeon chest] or
pectus excavatum A ); hypermobile joints; long, tapering fingers and toes (arachnodactyly); cystic
medial necrosis of aorta; aortic root aneurysm rupture or dissection (most common cause of
death); mitral valve prolapse; risk of spontaneous pneumothorax.
Homocystinuria—most commonly due to cystathionine synthase deficiency leading to
homocysteine buildup. Presentation similar to Marfan syndrome with pectus deformity, tall
stature, arm:height ratio, upper:lower body segment ratio, arachnodactyly, joint hyperlaxity,
skin hyperelasticity, scoliosis, fair complexion (vs Marfan syndrome).
Marfan syndrome Homocystinuria
INHERITANCE Autosomal dominant Autosomal recessive
INTELLECT Normal Decreased
VASCULAR COMPLICATIONS Aortic root dilatation Thrombosis
LENS DISLOCATION Upward/temporal (Marfan fans out) Downward/nasal
BIOCHEMISTRY—LABORATORY TECHNIQUES
`
Polymerase chain Molecular biology lab procedure used to amplify a desired fragment of DNA. Useful as a diagnostic
reaction tool (eg, neonatal HIV, herpes encephalitis).
5' 3' 5' 3' 5' 3'
5' 3' 3' 5'

DNA primer
dNTP
Repeat
3' 5' 5' 3'
Double-stranded DNA
3' 5' 3' 5' 3' 5'
Denaturation—DNA template, DNA primers, a heat-stable DNA polymerase, and

deoxynucleotide triphosphates (dNTPs) are heated to ~ 95ºC to separate the DNA strands.
Annealing—sample is cooled to ~ 55ºC. DNA primers anneal to the specific sequence to be
amplified on the DNA template.
Elongation—temperature is increased to ~ 72ºC. DNA polymerase adds dNTPs to the strand to
replicate the sequence after each primer.
Heating and cooling cycles continue until the amount of DNA is sufficient.

Biochemistry 
Biochemistry—Laboratory Techniques SEC TION II 51
CRISPR/Cas9 A genome editing tool derived from bacteria. Consists of a guide RNA (gRNA) , which is
complementary to a target DNA sequence, and an endonuclease (Cas9), which makes a single- or
double-strand break at the target site . Imperfectly cut segments are repaired by nonhomologous
end joining (NHEJ) accidental frameshift mutations (“knock-out”) , or a donor DNA
sequence can be added to fill in the gap using homology-directed repair (HDR) .
Potential applications include removing virulence factors from pathogens, replacing disease-causing
alleles of genes with healthy variants (in clinical trials for sickle cell disease), and specifically targeting
tumor cells.
Cas9 gRNA
Donor DNA
NHEJ 3A 3B HDR
+
Frameshift/inactivation Edited sequence

(”knock-out”) (”knock-in”)
Blotting procedures
Southern blot 1. DNA sample is enzymatically cleaved into I: Parents
smaller pieces, which are separated by gel
PEDIGREE
electrophoresis, and then transferred to a

membrane.
II: Children
2. Membrane is exposed to labeled DNA probe
that anneals to its complementary strand. Aa Aa aa Aa AA Genotype
3. Resulting double-stranded, labeled piece
SOUTHERN BLOT
of DNA is visualized when membrane is Mutant
exposed to film or digital imager. Normal
Useful to identify size of specific sequences

(eg, determination of heterozygosity [as seen SNoW DRoP:
in image], # of CGG repeats in FMR1 to Southern = DNA
diagnose Fragile X syndrome) Northern = RNA
Western = Protein
Northern blot Similar to Southern blot, except that an RNA sample is electrophoresed. Useful for studying
mRNA levels and size, which are reflective of gene expression. Detects splicing errors.
Western blot Sample protein is separated via gel electrophoresis and transferred to a membrane. Labeled antibody is
used to bind relevant protein. This helps identify specific protein and determines quantity.
Southwestern blot Identifies DNA-binding proteins (eg, c-Jun, c-Fos [leucine zipper motif]) using labeled double-
stranded DNA probes.
Southern (DNA) + Western (protein) = Southwestern (DNA-binding protein).

Biochemistry—Laboratory Techniques
Flow cytometry Laboratory technique to assess size, granularity, Fluorescent

label
and protein expression (immunophenotype) of
Antibody
individual cells in a sample.
Cells are tagged with antibodies specific to
surface or intracellular proteins. Antibodies Anti-CD3 Ab Cell
are then tagged with a unique fluorescent

dye. Sample is analyzed one cell at a time by Anti-CD8 Ab
Laser
focusing a laser on the cell and measuring Fluorescence
is detected; r Laser makes
light scatter and intensity of fluorescence. labeled cells te cto label fluoresce
De
Data are plotted either as histogram (one are counted
measure) or scatter plot (any two measures, as
shown). In illustration:
Cells in left lower quadrant ⊝ for both CD8 104
and CD3.
Cells in right lower quadrant ⊕ for CD8 103
and ⊝ for CD3. In this example, right
lower quadrant is empty because all
CD3
102
CD8-expressing cells also express CD3.
Cells in left upper quadrant ⊕ for CD3 and 101
⊝ for CD8.
Cells in right upper quadrant ⊕ for both 100
100 101 102 103 104
CD8 and CD3. CD8
Commonly used in workup of hematologic
abnormalities (eg, leukemia, paroxysmal
nocturnal hemoglobinuria, fetal
RBCs in pregnant person’s blood) and
immunodeficiencies (eg, CD4+ cell count in
HIV).
Microarrays Array consisting of thousands of DNA oligonucleotides arranged in a grid on a glass or silicon chip.
The DNA or RNA samples being compared are attached to different fluorophores and hybridized
to the array. The ratio of fluorescence signal at a particular oligonucleotide reflects the relative
amount of the hybridizing nucleic acid in the two samples.
Used to compare the relative transcription of genes in two RNA samples. Can detect single nucleotide
polymorphisms (SNPs) and copy number variants (CNVs) for genotyping, clinical genetic testing,
forensic analysis, and cancer mutation and genetic linkage analysis when DNA is used.
Enzyme-linked Immunologic test used to detect the presence Direct ELISA Substrate
Enzyme
immunosorbent assay of either a specific antigen or antibody in a Detectable
signal
patient’s blood sample. Detection involves Labeled 1° antibody
the use of an antibody linked to an enzyme.

Added substrate reacts with the enzyme, Antigen
producing a detectable signal. Can have high Substrate

Indirect ELISA
sensitivity and specificity, but is less specific
than Western blot. Often used to screen for Labeled 2° antibody
HIV infection.
1° antibody
Antigen

Biochemistry 
Biochemistry—Laboratory Techniques SEC TION II 53
Karyotyping Colchicine is added to cultured cells to halt A

chromosomes in metaphase. Chromosomes
are stained, ordered, and numbered according
to morphology, size, arm-length ratio, and
banding pattern (arrows in A point to extensive
abnormalities in a cancer cell).
Can be performed on a sample of blood, bone
marrow, amniotic fluid, or placental tissue.
Used to diagnose chromosomal imbalances
(eg, autosomal trisomies, sex chromosome
disorders).
Fluorescence in situ Fluorescent DNA or RNA probe binds to A

hybridization specific gene or other site of interest on
chromosomes.
Used for specific localization of genes and direct
visualization of chromosomal anomalies.
Microdeletion—no fluorescence on a
chromosome compared to fluorescence at
the same locus on the second copy of that
chromosome.
Translocation— A fluorescence signal
(from ABL gene) that corresponds to one
chromosome (chromosome 9) is found in a
different chromosome (chromosome 22, next
to BCR gene).
Duplication—a second copy of a
chromosome, resulting in a trisomy or
tetrasomy.
Molecular cloning Production of a recombinant DNA molecule in a bacterial host. Useful for production of human
proteins in bacteria (eg, human growth hormone, insulin).
Steps:
1. Isolate eukaryotic mRNA (post-RNA processing) of interest.
2. Add reverse transcriptase (an RNA-dependent DNA polymerase) to produce complementary
DNA (cDNA, lacks introns).
3. Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes.
4. Transform (insert) recombinant plasmid into bacteria.
5. Surviving bacteria on antibiotic medium produce cloned DNA (copies of cDNA).

BIOCHEMISTRY—Genetics
Gene expression Transgenic strategies in mice involve: Knock-out = removing a gene, taking it out.
modifications Random insertion of gene into mouse Knock-in = inserting a gene.
genome
Targeted insertion or deletion of gene Random insertion—constitutive expression.
through homologous recombination with Targeted insertion—conditional expression.
mouse gene
RNA interference Process whereby small non-coding RNA molecules target mRNAs to inhibit gene expression.
MicroRNA Naturally produced by cell as hairpin structures. Abnormal expression of miRNAs contributes
Loose nucleotide pairing allows broad to certain malignancies (eg, by silencing an
targeting of related mRNAs. When miRNA mRNA from a tumor suppressor gene).
binds to mRNA, it blocks translation of mRNA
and sometimes facilitates its degradation.
Small interfering Usually derived from exogenous dsRNA source Can be produced by transcription or
RNA (eg, virus). Once inside a cell, siRNA requires chemically synthesized for gene “knockdown”
complete nucleotide pairing, leading to highly experiments.
specific mRNA targeting. Results in mRNA
cleavage prior to translation.
BIOCHEMISTRY—GENETICS
`
Genetic terms
TERM DEFINITION EXAMPLE
Codominance Both alleles contribute to the phenotype of the Blood groups A, B, AB; α1-antitrypsin
heterozygote. deficiency; HLA groups.
Variable expressivity Patients with the same genotype have varying Two patients with neurofibromatosis type 1 (NF1)
phenotypes. may have varying disease severity.
Incomplete Not all individuals with a disease show the BRCA1 gene mutations do not always result in
penetrance disease. breast or ovarian cancer.
% penetrance × probability of inheriting
genotype = risk of expressing phenotype.
Pleiotropy One gene contributes to multiple phenotypic Untreated phenylketonuria (PKU) manifests with
effects. light skin, intellectual disability, musty body odor.
Anticipation Increased severity or earlier onset of disease in Trinucleotide repeat diseases (eg, Huntington
succeeding generations. disease).
Loss of heterozygosity If a patient inherits or develops a mutation in Retinoblastoma and the “two-hit hypothesis,”
a tumor suppressor gene, the wild type allele Lynch syndrome (HNPCC), Li-Fraumeni
must be deleted/mutated/eliminated before syndrome.
cancer develops. This is not true of oncogenes.
Epistasis The allele of one gene affects the phenotypic Albinism, alopecia.
expression of alleles in another gene.
Aneuploidy An abnormal number of chromosomes; due to Down syndrome, Turner syndrome,
chromosomal nondisjunction during mitosis oncogenesis.
or meiosis.

Biochemistry 
BIOCHEMISTRY—Genetics SEC TION II 55
Genetic terms (continued)

TERM DEFINITION EXAMPLE
Dominant negative Exerts a dominant effect. A heterozygote A single mutated p53 tumor suppressor gene
mutation produces a nonfunctional altered protein that results in a protein that is able to bind DNA
also prevents the normal gene product from and block the wild type p53 from binding to the
functioning. promoter.
Linkage Tendency for certain alleles to occur in close
disequilibrium proximity on the same chromosome more or
less often than expected by chance. Measured
in a population, not in a family, and often
varies in different populations.
Mosaicism Presence of genetically distinct cell lines in the McCune-Albright syndrome—due to Gs-protein
A
same individual. activating mutation. Presents with unilateral
Somatic mosaicism—mutation arises from café-au-lait spots A with ragged edges,
mitotic errors after fertilization and propagates polyostotic fibrous dysplasia (bone is replaced
through multiple tissues or organs. by collagen and fibroblasts), and at least one
Germline (gonadal) mosaicism—mutation only endocrinopathy (eg, precocious puberty).
in egg or sperm cells. If parents and relatives Lethal if mutation occurs before fertilization
do not have the disease, suspect gonadal (or (affecting all cells), but survivable in patients
germline) mosaicism. with mosaicism.
Locus heterogeneity Mutations at different loci result in the same Albinism, retinitis pigmentosa, familial
disease. hypercholesteremia.
Allelic heterogeneity Different mutations in the same locus result in β-thalassemia.
the same disease.
Heteroplasmy Presence of both normal and mutated mtDNA passed from mother to all children.
mtDNA, resulting in variable expression in
mitochondrially inherited disease.
Uniparental disomy Offspring receives 2 copies of a chromosome from Uniparental is euploid (correct number of
1 parent and no copies from the other parent. chromosomes). Most occurrences of uniparental
HeterodIsomy (heterozygous) indicates a meiosis disomy (UPD) normal phenotype. Consider
I error. IsodIsomy (homozygous) indicates a isodisomy in an individual manifesting a
meiosis II error or postzygotic chromosomal recessive disorder when only one parent is a
duplication of one of a pair of chromosomes, carrier. Examples: Prader-Willi and Angelman
and loss of the other of the original pair. syndromes.
Population genetics
CONCEPT DESCRIPTION EXAMPLE
Bottleneck effect Fitness equal across alleles natural disaster that The founder effect is a type of bottleneck
removes certain alleles by chance new allelic when cause is due to calamitous population
frequency (by chance, not naturally selected). separation.
Natural selection Alleles that increase species fitness are more likely Human evolution.
to be passed down to offspring and vice versa.
Genetic drift Also called allelic drift or Wright effect. A Founder effect and bottleneck effect are both
dramatic shift in allelic frequency that occurs examples of genetic drift.
by change (not by natural selection).

Hardy-Weinberg In a given population where mating is at If a population is in Hardy-Weinberg

principle random, allele and genotype frequencies equilibrium, then the values of p and q remain
will be constant. If p and q represent the constant from generation to generation.
A (p) a (q)
frequencies of alleles A and a in a population, In rare autosomal recessive diseases, p ≈ 1.
AA Aa
A (p)
(p2) (pq) respectively, then p + q = 1, where: Example: The prevalence of cystic fibrosis
Aa aa
p2 = frequency of homozygosity for allele A (an autosomal recessive disease) in the US
a (q) q2 = frequency of homozygosity for allele a is approximately 1/3200, which tells us that
(pq) (q2)
2pq = frequency of heterozygosity (carrier q2 = 1/3200, with q ≈ 0.017 or 1.7% of the
frequency, if an autosomal recessive disease) population. Since p + q = 1, we know that
Therefore the sum of the frequencies of these p = 1 – √1/3200 ≈ 0.982, which gives us a
genotypes is p2 + 2pq + q2 = 1. heterozygous carrier frequency of 2pq = 0.035
The frequency of an X-linked recessive disease or 3.5% of the population. Notice that since
in males = q and in females = q2. the disease is relatively rare, we could have
Hardy-Weinberg law assumptions include: approximated p ≈ 1 and obtained a similar
No mutation occurring at the locus result.
Natural selection is not occurring
Completely random mating
No net migration
Large population
Disorders of imprinting One gene copy is silenced by methylation, and only the other copy is expressed parent-of-origin
effects. The expressed copy may be mutated, may not be expressed, or may be deleted altogether.
Prader-Willi syndrome Angelman syndrome
WHICH GENE IS SILENT? Maternally derived genes are silenced Paternally derived UBE3A is silenced
Disease occurs when the paternal allele is deleted Disease occurs when the maternal allele is
or mutated deleted or mutated
SIGNS AND SYMPTOMS Hyperphagia, obesity, intellectual disability, Hand-flapping, Ataxia, severe Intellectual
hypogonadism, hypotonia disability, inappropriate Laughter, Seizures.
HAILS the Angels.
CHROMOSOMES INVOLVED Chromosome 15 of paternal origin UBE3A on maternal copy of chromosome 15
NOTES 25% of cases are due to maternal uniparental 5% of cases are due to paternal uniparental
disomy disomy
POP: Prader-Willi, Obesity/overeating, Paternal MAMAS: Maternal allele deleted, Angelman
allele deleted syndrome, Mood, Ataxia, Seizures
P = Paternal
M = Maternal
Normal Mutation
Active gene
P M P M
Silenced gene (imprinting)
Gene deletion/mutation
Prader-Willi syndrome
Angelman syndrome

Biochemistry 
Modes of inheritance
Autosomal dominant Often due to defects in structural genes. Many Often pleiotropic (multiple apparently unrelated
generations, both males and females are affected. effects) and variably expressive (different
A a between individuals). Family history crucial
to diagnosis. With one affected (heterozygous)
a Aa aa
parent, each child has a 50% chance of being
a Aa aa
affected.
Autosomal recessive With 2 carrier (heterozygous) parents, on average: Often due to enzyme deficiencies. Usually seen
each child has a 25% chance of being affected, in only 1 generation. Commonly more severe
50% chance of being a carrier, and 25% chance than dominant disorders; patients often present
of not being affected nor a carrier. in childhood.
A a risk in consanguineous families.
Unaffected individual with affected sibling has
A AA Aa
2/3 probability of being a carrier.
a Aa aa
X-linked recessive Sons of heterozygous mothers have a 50% Commonly more severe in males. Females
chance of being affected. No male-to-male usually must be homozygous to be affected.
carrier transmission. Skips generations.
X X X X
X XX XX X XX XX
Y XY XY Y XY XY
X-linked dominant Transmitted through both parents. Children of Examples: fragile X syndrome, Alport syndrome,
affected mothers each have a 50% chance of hypophosphatemic rickets (also called X-linked
being affected. 100% of daughters and 0% of hypophosphatemia)—phosphate wasting at
sons of affected fathers will be affected. proximal tubule ricketslike presentation.
X X X X
X XX XX X XX XX
Y XY XY Y XY XY
Mitochondrial Transmitted only through the mother. All Caused by mutations in mtDNA.
inheritance offspring of affected females may show signs of Examples: mitochondrial myopathies, Leber
disease. hereditary optic neuropathy.
Variable expression in a population or even
within a family due to heteroplasmy.
= unaffected male; = affected male; = unaffected female; = affected female.

Autosomal dominant Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,
diseases familial hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
syndrome), hereditary spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome,
multiple endocrine neoplasias, myotonic muscular dystrophy, neurofibromatosis type 1 (von
Recklinghausen disease), neurofibromatosis type 2, tuberous sclerosis, von Hippel-Lindau disease.
Autosomal recessive Mostly consist of enzyme defects. Oculocutaneous albinism, phenylketonuria, cystic fibrosis, sickle
diseases cell disease, Wilson disease, sphingolipidoses (except Fabry disease), hemochromatosis, glycogen
storage diseases, thalassemia, mucopolysaccharidoses (except Hunter syndrome), Friedreich
ataxia, Kartagener syndrome, ARPKD. Oh, please! Can students who score high grades tell me
features of the kidney disorder Autosomal Recessive Polycystic Kidney Disease?
Cystic fibrosis
GENETICS Autosomal recessive; defect in CFTR gene on chromosome 7 (deletion; ΔF508). Most common
lethal genetic disease in patients with European ancestry.
PATHOPHYSIOLOGY CFTR encodes an ATP-gated Cl− channel (secretes Cl− in lungs/GI tract, reabsorbs Cl− in sweat
glands). Phe508 deletion misfolded protein improper protein trafficking protein absent
from cell membrane Cl− (and H2O) secretion compensatory Na+ reabsorption via
epithelial Na+ channels (ENaC) H2O reabsorption abnormally thick mucus secreted into
lungs/GI tract. Na+ reabsorption = more negative transepithelial potential difference.
DIAGNOSIS Cl− concentration in pilocarpine-induced sweat test. Can present with contraction alkalosis
and hypokalemia (ECF effects analogous loop diuretic effect) due to ECF H2O/Na+ losses
via sweating and concomitant renal K+/H+ wasting. immunoreactive trypsinogen (newborn
screening) due to clogging of pancreatic duct.
COMPLICATIONS Recurrent pulmonary infections (eg, S aureus [infancy and early childhood], P aeruginosa
[adulthood], allergic bronchopulmonary aspergillosis [ABPA]), chronic bronchitis and bronchiectasis
reticulonodular pattern on CXR, opacification of sinuses. Nasal polyps, nail clubbing.
Pancreatic insufficiency, malabsorption with steatorrhea, and fat-soluble vitamin deficiencies (A, D,
E, K) progressing to endocrine dysfunction (CF-related diabetes), biliary cirrhosis, liver disease.
Meconium ileus in newborns.
Infertility in males (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in
females (amenorrhea, abnormally thick cervical mucus).
TREATMENT Multifactorial: chest physiotherapy, aerosolized dornase alfa (DNase), and inhaled hypertonic saline
mucus clearance. Azithromycin prevents acute exacerbations. Ibuprofen for anti-inflammatory
effect. Pancreatic enzyme replacement therapy (pancrelipase) for pancreatic insufficiency.
CFTR modulators can be used alone or in combination. Efficacy varies by different genetic
mutations (pharmacogenomics). Are either potentiators (hold gate of CFTR channel open Cl−
flows through cell membrane; eg, ivacaftor) or correctors (help CFTR protein to form right 3-D
shape moves to the cell surface; eg, lumacaftor, tezacaftor).
Normal mucus Dehydrated mucus

CI– Na+ CI– Na+
CFTR ENaC Lumen
CI–
CI– H₂O Na+ H₂O Na+
Interstitium
Normal Sweat duct CF Normal Airway CF

Biochemistry 
X-linked recessive Bruton agammaglobulinemia, Duchenne and Becker muscular dystrophies, Fabry disease, G6PD
diseases deficiency, hemophilia A and B, Hunter syndrome, Lesch-Nyhan syndrome, ocular albinism,
ornithine transcarbamylase (OTC) deficiency, Wiskott-Aldrich syndrome.
Females with Turner syndrome (45,XO) are more likely to have an X-linked recessive disorder.
X-inactivation (lyonization)—during development, one of the X chromosomes in each XX cell
is randomly deactivated and condensed into a Barr body (methylated heterochromatin). If
skewed inactivation occurs, XX individuals may express X-linked recessive diseases (eg, G6PD);
penetrance and severity of X-linked dominant diseases in XX individuals may also be impacted.
Muscular dystrophies
Duchenne X-linked recessive disorder typically due to Duchenne = deleted dystrophin.
A
frameshift deletions or nonsense mutations Dystrophin gene (DMD) is the largest
Muscle fibers truncated or absent dystrophin protein protein-coding human gene chance of
progressive myofiber damage. Can also spontaneous mutation. Dystrophin helps
result from splicing errors. to anchor muscle fibers to the extracellular
Weakness begins in pelvic girdle muscles and matrix, primarily in skeletal and cardiac
progresses superiorly. Pseudohypertrophy of muscles. Loss of dystrophin myonecrosis.
calf muscles due to fibrofatty replacement of CK and aldolase; genetic testing confirms
muscle A . Waddling gait. diagnosis.
Onset before 5 years of age. Dilated Calf
cardiomyopathy is common cause of death. pseudohypertrophy
Gowers sign—patient uses upper extremities to

help stand up. Classically seen in Duchenne
muscular dystrophy, but also seen in other
Lordosis
muscular dystrophies and inflammatory
myopathies (eg, polymyositis). Thigh
atrophy
Pushing on leg
to stand
Becker X-linked recessive disorder typically due to Deletions can cause both Duchenne and
non-frameshift deletions in dystrophin gene Becker muscular dystrophies. 2⁄3 of cases have
(partially functional instead of truncated). large deletions spanning one or more exons.
Less severe than Duchenne (Becker is better).
Onset in adolescence or early adulthood.
Myotonic dystrophy Autosomal dominant. Onset 20–30 years. CTG Cataracts, Toupee (early balding in males),
trinucleotide repeat expansion in the DMPK Gonadal atrophy.
gene abnormal expression of myotonin
protein kinase myotonia (eg, difficulty
releasing hand from handshake), muscle
wasting, cataracts, testicular atrophy, frontal
balding, arrhythmia.

Mitochondrial diseases Rare disorders arising 2° to failure in oxidative phosphorylation. Tissues with energy requirements
are preferentially affected (eg, CNS, skeletal muscle).
Mitochondrial myopathies—include MELAS (mitochondrial encephalomyopathy with lactic
acidosis and strokelike episodes) and MERRF (myoclonic epilepsy with ragged red fibers). Light
microscopy with stain: ragged red fibers due to compensatory proliferation of mitochondria.
Electron microscopy: mitochondrial crystalline inclusions.
Leber hereditary optic neuropathy—mutations in complex I of ETC neuronal death in retina
and optic nerve subacute bilateral vision loss in teens/young adults (males > females). Usually
permanent. May be accompanied by neurologic dysfunction (eg, tremors, multiple sclerosis–like
illness).
Rett syndrome Sporadic disorder caused by de novo mutation of MECP2 on X chromosome. Seen mostly in
females. Embryonically lethal in males. Individuals with Rett syndrome experience initial normal
development (6–18 months) followed by regression (“retturn”) in motor, verbal, and cognitive
abilities; ataxia; seizures; scoliosis; and stereotypic hand-wringing.
Fragile X syndrome X-linked dominant inheritance. Trinucleotide Trinucleotide repeat expansion [(CGG)n] occurs
repeats in FMR1 hypermethylation of during oogenesis.
cytosine residues expression. Premutation (50–200 repeats) tremor, ataxia,
Most common inherited cause of intellectual 1° ovarian insufficiency.
disability (Down syndrome is most common Full mutation (>200 repeats) postpubertal
genetic cause, but most cases occur macroorchidism (enlarged testes), long face
sporadically). with large jaw, large everted ears, autism,
mitral valve prolapse, hypermobile joints.
Self-mutilation is common and can be confused
with Lesch-Nyhan syndrome.
Trinucleotide repeat May show genetic anticipation (disease severity and age of onset in successive generations).
expansion diseases
DISEASE TRINUCLEOTIDE REPEAT MODE OF INHERITANCE MNEMONIC
Huntington disease (CAG)n AD Caudate has ACh and GABA
Myotonic dystrophy (CTG)n AD Cataracts, Toupee (early balding in males),
Gonadal atrophy in males, reduced fertility in
females
Fragile X syndrome (CGG)n XD Chin (protruding), Giant Gonads
Friedreich ataxia (GAA)n AR Ataxic GAAit

Biochemistry 
Autosomal trisomies Autosomal trisomies are screened in first and second trimesters with noninvasive prenatal tests.
Incidence of trisomies: Down (21) > Edwards (18) > Patau (13). Autosomal monosomies are
incompatible with life (high chance of recessive trait expression).
Down syndrome Findings: intellectual disability, flat facies, Drinking age (21).
(trisomy 21) prominent epicanthal folds, single palmar Most common viable chromosomal disorder
crease, incurved 5th finger, gap between 1st 2 and most common cause of genetic
toes, duodenal atresia, Hirschsprung disease, intellectual disability.
congenital heart disease (eg, AVSD), Brushfield First-trimester ultrasound commonly shows
spots (whitish spots at the periphery of the iris). nuchal translucency and hypoplastic nasal
Associated with early-onset Alzheimer disease bone. Markers for Down syndrome are hi up:
(chromosome 21 codes for amyloid precursor hCG, inhibin.
protein), risk of AML/ALL. risk of umbilical hernia (incomplete closure of
95% of cases due to meiotic nondisjunction, umbilical ring).
most commonly during meiosis I ( with The 5 A’s of Down syndrome:
Single palmar crease advanced maternal age: from 1:1500 in females Advanced maternal age
< 20 to 1:25 in females > 45). 4% of cases due to Atresia (duodenal)
unbalanced Robertsonian translocation, most Atrioventricular septal defect
typically between chromosomes 14 and 21. 1% Alzheimer disease (early onset)
of cases due to postfertilization mitotic error. AML (<5 years of age)/ALL (>5 years of age)
Edwards syndrome Findings: PRINCE Edward—Prominent Election age (18).
(trisomy 18) occiput, Rocker-bottom feet, Intellectual 2nd most common autosomal trisomy resulting
disability, Nondisjunction, Clenched fists with in live birth (most common is Down syndrome).
overlapping fingers, low-set Ears, micrognathia In Edwards syndrome, every prenatal screening
(small jaw), congenital heart disease (eg, marker decreases.
VSD), omphalocele, myelomeningocele.
Death usually occurs by age 1.
Patau syndrome Findings: severe intellectual disability, rocker- Puberty at age 13.
(trisomy 13) bottom feet, microphthalmia, microcephaly, Defect in fusion of prechordal mesoderm
cleft lip/palate, holoprosencephaly, midline defects.
polydactyly, cutis aplasia, congenital heart
(pump) disease, polycystic kidney disease,
omphalocele. Death usually occurs by age 1.
Cutis aplasia
Nondisjunction in meiosis I Nondisjunction in meiosis II 1st trimester screening

Trisomy β-hCG PAPP-A
Meiosis I 21
18
Nondisjunction 13
Meiosis II 2nd trimester (quadruple) screening

Trisomy hCG Inhibin A Estriol AFP
Nondisjunction
21
18 — or
Gametes
13 — — — —
n+1 n+1 n–1 n–1 n n n–1 n+1
Trisomy Monosomy Normal Monosomy Trisomy

Genetic disorders by CHROMOSOME SELECTED EXAMPLES
chromosome 3 von Hippel-Lindau disease, renal cell carcinoma

4 ADPKD (PKD2), achondroplasia, Huntington disease
5 Cri-du-chat syndrome, familial adenomatous polyposis
6 Hemochromatosis (HFE)
7 Williams syndrome, cystic fibrosis
9 Friedreich ataxia, tuberous sclerosis (TSC1)
11 Wilms tumor, β-globin gene defects (eg, sickle cell disease, β-thalassemia), MEN1
13 Patau syndrome, Wilson disease, retinoblastoma (RB1), BRCA2
15 Prader-Willi syndrome, Angelman syndrome, Marfan syndrome
16 ADPKD (PKD1), α-globin gene defects (eg, α-thalassemia), tuberous sclerosis (TSC2)
17 Neurofibromatosis type 1, BRCA1, TP53 (Li-Fraumeni syndrome)
18 Edwards syndrome
21 Down syndrome
22 Neurofibromatosis type 2, DiGeorge syndrome (22q11)
X Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)
Robertsonian Chromosomal translocation that commonly involves chromosome pairs 21, 22, 13, 14, and 15.
translocation One of the most common types of translocation. Occurs when the long arms of 2 acrocentric
chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the
2 short arms are lost.
Balanced translocations (no gain or loss of significant genetic material) normally do not cause
abnormal phenotype. Unbalanced translocations (missing or extra genes) can result in
miscarriage, stillbirth, and chromosomal imbalance (eg, Down syndrome, Patau syndrome).
Normal Robertsonian Unbalanced gamete
gamete precursor translocation precursor
Meiosis Meiosis
Normal gamete Normal gamete Abnormal gametes
Cri-du-chat syndrome Cri du chat = cry of the cat. Congenital deletion on short arm of chromosome 5 (46,XX or XY, 5p−).
Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying, epicanthal
folds, cardiac abnormalities (VSD). I cry when I am Very SaD.

Biochemistry 
BIOCHEMISTRY—Nutrition SEC TION II 63
Williams syndrome Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene).
Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia, well-developed verbal
skills, extreme friendliness with strangers, cardiovascular problems (eg, supravalvular aortic
stenosis, renal artery stenosis).
BIOCHEMISTRY—NUTRITION
`
Essential fatty acids Polyunsaturated fatty acids that cannot be In contrast, consumption of trans-unsaturated
synthesized in the body and must be provided fatty acids (found in fast food) promotes
in the diet (eg, nuts/seeds, plant oils, seafood). cardiovascular disease by LDL and HDL.
Linoleic acid (omega-6) is metabolized to
arachidonic acid, which serves as the precursor
to leukotrienes and prostaglandins.
Linolenic acid (omega-3) and its metabolites
have cardioprotective and antihyperlipidemic
effects.
Vitamins: fat soluble A, D, E, K. Absorption dependent on bile Malabsorption syndromes with steatorrhea (eg,
emulsification, pancreatic secretions, and cystic fibrosis and celiac disease) or mineral
intact ileum. Toxicity more common than oil intake can cause fat-soluble vitamin
for water-soluble vitamins because fat-soluble deficiencies.
vitamins accumulate in fat.
Vitamins: water B1 (thiamine: TPP) Wash out easily from body except B12 and B9.
soluble B2 (riboflavin: FAD, FMN) B12 stored in liver for ~ 3–4 years. B9 stored in
B3 (niacin: NAD+) liver for ~ 3–4 months.
B5 (pantothenic acid: CoA) B-complex deficiencies often result in
B6 (pyridoxine: PLP) dermatitis, glossitis, and diarrhea.
B7 (biotin) Can be coenzymes (eg, ascorbic acid) or
B9 (folate) precursors to coenzymes (eg, FAD, NAD+).
B12 (cobalamin)
C (ascorbic acid)
Dietary DIET SUPPLEMENTATION REQUIRED
supplementation Vegetarian/vegan Vitamin B12

Iron
Vitamin B2
Frequently, vitamin D (although this is commonly deficient in many diets)
High egg white (raw) Vitamin B7 (avidin in egg whites binds biotin and prevents absorption)
Untreated corn Vitamin B3 (deficiency is common in resource-limited areas)

BIOCHEMISTRY—Nutrition
Vitamin A Includes retinal, retinol, retinoic acid.

FUNCTION Antioxidant; constituent of visual pigments Retinol is vitamin A, so think retin-A (used
(retinal); essential for normal differentiation topically for wrinkles and Acne).
of epithelial cells into specialized tissue Found in liver and leafy vegetables.
(pancreatic cells, mucus-secreting cells); Supplementation in vitamin A-deficient measles
prevents squamous metaplasia. patients may improve outcomes.
Use oral isotretinoin to treat severe cystic acne.
Use all-trans retinoic acid to treat acute
promyelocytic leukemia.
DEFICIENCY Night blindness (nyctalopia); dry, scaly skin

A
(xerosis cutis); dry eyes (xerophthalmia);
conjunctival squamous metaplasia Bitot
spots (keratin debris; foamy appearance
on conjunctiva A ); corneal degeneration
(keratomalacia); immunosuppression.
EXCESS Acute toxicity—nausea, vomiting, ICP (eg, Teratogenic (interferes with homeobox gene; cleft
vertigo, blurred vision). palate, cardiac abnormalities), therefore a ⊝
Chronic toxicity—alopecia, dry skin (eg, pregnancy test and two forms of contraception
scaliness), hepatic toxicity and enlargement, are required before isotretinoin (vitamin A
arthralgias, and idiopathic intracranial derivative) is prescribed.
hypertension. Isotretinoin is teratogenic.
Vitamin B1 Also called thiamine.

FUNCTION In thiamine pyrophosphate (TPP), a cofactor for several dehydrogenase enzyme reactions (Be APT):
Branched-chain ketoacid dehydrogenase
α-Ketoglutarate dehydrogenase (TCA cycle)
Pyruvate dehydrogenase (links glycolysis to TCA cycle)
Transketolase (HMP shunt)
DEFICIENCY Impaired glucose breakdown ATP depletion worsened by glucose infusion; highly aerobic tissues
(eg, brain, heart) are affected first. In patients with chronic alcohol overuse or malnutrition, give
thiamine before dextrose to risk of precipitating Wernicke encephalopathy.
Diagnosis made by in RBC transketolase activity following vitamin B1 administration.
DISORDER CHARACTERISTICS
Wernicke Acute, reversible, life-threatening neurologic condition. Symptoms: Confusion, Ophthalmoplegia/
encephalopathy Nystagmus, Ataxia (CorONA beer).
Korsakoff syndrome Amnestic disorder due to chronic alcohol overuse; presents with confabulation, personality
changes, memory loss (permanent).
Wernicke-Korsakoff Damage to medial dorsal nucleus of thalamus, mammillary bodies. Presentation is combination of
syndrome Wernicke encephalopathy and Korsakoff syndrome.
Dry beriberi Polyneuropathy, symmetric muscle wasting. Spell beriberi as Ber1Ber1 to remember
Wet beriberi High-output cardiac failure (due to systemic vitamin B1.
vasodilation).

Biochemistry 
Vitamin B2 Also called riboflavin.

FUNCTION Component of flavins FAD and FMN, used as FAD and FMN are derived from riboFlavin
cofactors in redox reactions, eg, the succinate (B2 ≈ 2 ATP).
dehydrogenase reaction in the TCA cycle.
DEFICIENCY Cheilosis (inflammation of lips, scaling The 2 C’s of B2.
and fissures at the corners of the mouth),
“magenta” tongue, corneal vascularization.
Vitamin B3 Also called niacin, nicotinic acid.

FUNCTION Constituent of NAD+, NADP+ (used in redox NAD derived from Niacin (B3 ≈ 3 ATP).
reactions and as cofactor by dehydrogenases).
Derived from tryptophan. Synthesis requires
vitamins B2 and B6. Used to treat dyslipidemia
( VLDL, HDL).
DEFICIENCY Glossitis. Severe deficiency of B3 leads to Hartnup disease—autosomal recessive.
A
pellagra, which can also be caused by Hartnup Deficiency of neutral amino acid (eg,
disease, malignant carcinoid syndrome tryptophan) transporters in proximal renal
( tryptophan metabolism serotonin tubular cells and on enterocytes neutral
synthesis), and isoniazid ( vitamin B6). aminoaciduria and absorption from the
Symptoms of B3 deficiency (pellagra) (the 3 gut tryptophan for conversion to niacin
D’s): diarrhea, dementia (also hallucinations), pellagra-like symptoms. Treat with high-
dermatitis (C3/C4 dermatome circumferential protein diet and nicotinic acid.
“broad collar” rash [Casal necklace], Pellagra = vitamin B3 levels fell.
hyperpigmentation of sun-exposed limbs A ).
EXCESS Facial flushing (induced by prostaglandin, not Podagra = vitamin B3 OD (overdose).

histamine; can avoid by taking aspirin before
niacin), hyperglycemia, hyperuricemia.
Vitamin B5 Also called pantothenic acid. B5 is “pento”thenic acid.

FUNCTION Component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase.
DEFICIENCY Dermatitis, enteritis, alopecia, adrenal insufficiency may lead to burning sensation of feet
(“burning feet syndrome”; distal paresthesias, dysesthesia).
Vitamin B6 Also called pyridoxine.

FUNCTION Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg, ALT and AST),
decarboxylation reactions, glycogen phosphorylase. Synthesis of glutathione, cystathionine, heme,
niacin, histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE),
dopamine, and GABA.
DEFICIENCY Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral
contraceptives), sideroblastic anemia (due to impaired hemoglobin synthesis and iron excess).

Vitamin B7 Also called biotin.

FUNCTION Cofactor for carboxylation enzymes (which add a 1-carbon group):
Pyruvate carboxylase (gluconeogenesis): pyruvate (3C) oxaloacetate (4C)
Acetyl-CoA carboxylase (fatty acid synthesis): acetyl-CoA (2C) malonyl-CoA (3C)
Propionyl-CoA carboxylase (fatty acid oxidation and branched-chain amino acid breakdown):
propionyl-CoA (3C) methylmalonyl-CoA (4C)
DEFICIENCY Relatively rare. Dermatitis, enteritis, alopecia. Caused by long-term antibiotic use or excessive
ingestion of raw egg whites.
“Avidin in egg whites avidly binds biotin.”
Vitamin B9 Also called folate.

FUNCTION Converted to tetrahydrofolic acid (THF), a Found in leafy green vegetables. Also produced
coenzyme for 1-carbon transfer/methylation by gut microbiota. Folate absorbed in jejunum
reactions. (think foliage in the “jejun”gle).
Important for the synthesis of nitrogenous bases Small reserve pool stored primarily in the liver.
in DNA and RNA.
DEFICIENCY Macrocytic, megaloblastic anemia; Deficiency can be caused by several drugs (eg,
hypersegmented polymorphonuclear cells phenytoin, trimethoprim, methotrexate).
(PMNs); glossitis; no neurologic symptoms (as Supplemental folic acid at least 1 month prior
opposed to vitamin B12 deficiency). to conception and during pregnancy to risk
Labs: homocysteine, normal methylmalonic of neural tube defects. Give vitamin B9 for the
acid levels. Seen in chronic alcohol overuse 9 months of pregnancy, and 1 month prior to
and in pregnancy. conception.

Biochemistry 
Vitamin B12 Also called cobalamin.

FUNCTION Cofactor for methionine synthase (transfers Found in animal products. Synthesized only
CH3 groups as methylcobalamin) and by intestinal microbiota. Site of synthesis in
methylmalonyl-CoA mutase. Important for humans is distal to site of absorption; thus B12
DNA synthesis. must be consumed via animal products.
DEFICIENCY Macrocytic, megaloblastic anemia; Very large reserve pool (several years) stored
hypersegmented PMNs; paresthesias primarily in the liver. Deficiency caused
and subacute combined degeneration by malabsorption (eg, sprue, enteritis,
(degeneration of dorsal columns, lateral Diphyllobothrium latum, achlorhydria,
corticospinal tracts, and spinocerebellar tracts) bacterial overgrowth, alcohol overuse), lack of
due to abnormal myelin. Associated with intrinsic factor (eg, pernicious anemia, gastric
serum homocysteine and methylmalonic bypass surgery), absence of terminal ileum
acid levels, along with 2° folate deficiency. (surgical resection, eg, for Crohn disease),
Prolonged deficiency irreversible nerve certain drugs (eg, metformin), or insufficient
damage. intake (eg, veganism).
B9 (folate) supplementation can mask the
hematologic symptoms of B12 deficiency, but
not the neurologic symptoms.
Protein Fatty acids with odd number of
carbons, branched-chain amino acids
THF Methionine SAM
CH3 to anabolic
pathways Methylmalonyl-CoA
Methylmalonyl-CoA
B12 Methionine synthase
S-adenosyl B12 mutase
homocysteine
Succinyl-CoA
B6
THF–CH3 Homocysteine
Heme TCA cycle
B6 Adenosine
Cysteine
Vitamin C Also called ascorbic acid.

FUNCTION Antioxidant; also facilitates iron absorption Found in fruits and vegetables.
by reducing it to Fe2+ state. Necessary Pronounce “absorbic” acid.
for hydroxylation of proline and lysine in Ancillary treatment for methemoglobinemia by
collagen synthesis. Necessary for dopamine reducing Fe3+ to Fe2+.
β-hydroxylase (converts dopamine to NE).
DEFICIENCY Scurvy—swollen gums, easy bruising, Deficiency may be precipitated by tea and toast
petechiae, hemarthrosis, anemia, poor wound diet.
healing, perifollicular and subperiosteal Vitamin C deficiency causes sCurvy due to a
hemorrhages, “corkscrew” hair. Collagen hydroCylation defect.
Weakened immune response.
EXCESS Nausea, vomiting, diarrhea, fatigue, calcium
oxalate nephrolithiasis (excess oxalate from
vitamin C metabolism). Can iron toxicity in
predisposed individuals by increasing dietary
iron absorption (ie, can worsen hemochromatosis
or transfusion-related iron overload).

Vitamin D D3 (cholecalciferol) from exposure of skin (stratum basale) to sun, ingestion of fish, milk, plants.
D2 (ergocalciferol) from ingestion of plants, fungi, yeasts.
Both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2 D3 (calcitriol)
in kidney.
FUNCTION intestinal absorption of Ca2+ and Cholesterol →
PO43–. Diet 7-dehydrocholesterol
bone mineralization at low levels. Sun/UV exposure
bone resorption at higher levels. D2 D3
2+ (Ergocalciferol) (Cholecalciferol)
REGULATION PTH, Ca , PO43–
1,25-(OH)2D3 production.
1,25-(OH)2D3 feedback inhibits its own
production. 25-hydroxylase
PTH Ca2+ reabsorption and
PO43– reabsorption in the kidney. 25-OH D 3
DEFICIENCY Rickets in children (deformity, such
A
↑ ↑
as genu varum “bowlegs” A ), Ca2+, PO43–
osteomalacia in adults (bone pain
and muscle weakness), hypocalcemic
tetany. 1α-hydroxylase
Caused by malabsorption, sun
exposure, poor diet, chronic kidney 1,25-(OH)2 D3
disease (CKD), advanced liver disease.
Give oral vitamin D to breastfed infants. Bone Intestines Renal tubular cells
Darker skin and prematurity predispose
to deficiency.
↑ Ca2+ and ↑ PO43– ↑ absorption of Reabsorption: ↑ Ca2+, ↑ PO43–
EXCESS Hypercalcemia, hypercalciuria, loss of
released from bone Ca2+ and PO43– Urine: Ca2+, PO43–
↑ ↑
appetite, stupor. Seen in granulomatous
diseases ( activation of vitamin D by
epithelioid macrophages). ↑ Ca2+ and ↑ PO43–
Vitamin E Includes tocopherol, tocotrienol.

FUNCTION Antioxidant (protects RBCs and
neuronal membranes from free radical damage).
DEFICIENCY Hemolytic anemia, acanthocytosis, muscle Neurologic presentation may appear similar
weakness, demyelination of posterior columns to vitamin B12 deficiency, but without
( proprioception and vibration sensation) and megaloblastic anemia, hypersegmented
spinocerebellar tract (ataxia). Closely mimics neutrophils, or serum methylmalonic acid
Friedreich ataxia. levels.
EXCESS Risk of enterocolitis in enfants (infants) with High-dose supplementation may alter metabolism
excess of vitamin E. of vitamin K enhanced anticoagulant effects
of warfarin.

Biochemistry 
Vitamin K Includes phytomenadione, phylloquinone, phytonadione, menaquinone.

FUNCTION Activated by epoxide reductase to the K is for Koagulation. Necessary for the
reduced form, which is a cofactor for the maturation of clotting factors II, VII, IX,
γ-carboxylation of glutamic acid residues on X, and proteins C and S. Warfarin inhibits
various proteins required for blood clotting. vitamin K–dependent synthesis of these factors
Synthesized by intestinal microbiota. and proteins.
DEFICIENCY Neonatal hemorrhage with PT and aPTT Not in breast milk; “breast-fed infants Don’t
but normal bleeding time (neonates have Know about vitamins D and K”. Neonates are
sterile intestines and are unable to synthesize given vitamin K injection at birth to prevent
vitamin K). Can also occur after prolonged use hemorrhagic disease of the newborn.
of broad-spectrum antibiotics or hepatocellular
disease.
Zinc
FUNCTION Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers
(transcription factor motif).
DEFICIENCY Delayed wound healing, suppressed immunity, male hypogonadism, adult hair (axillary, facial,
A pubic), dysgeusia, anosmia. Associated with acrodermatitis enteropathica A (congenital defect in
intestinal zinc absorption manifesting with triad of hair loss, diarrhea, and inflammatory skin rash
around body openings (periorificial) and tips of fingers/toes (acral). May predispose to alcoholic
cirrhosis.
Protein-energy malnutrition
Kwashiorkor Protein malnutrition resulting in skin lesions, A B
edema due to plasma oncotic pressure (due
to low serum albumin), liver malfunction
(fatty change due to apolipoprotein synthesis
and deposition). Clinical picture is small child
with swollen abdomen A .
Kwashiorkor results from protein-
deficient MEALS:
Malnutrition
Edema
Anemia
Liver (fatty)
Skin lesions (eg, hyperkeratosis,
dyspigmentation)
Marasmus Malnutrition not causing edema. Diet is Linear growth maintained in acute protein-
deficient in calories but no nutrients are energy malnutrition (vs chronic malnutrition).
entirely absent.
Marasmus results in muscle wasting B .

Ethanol metabolism
NADH/NAD+ ratio inhibits
NADPH NADP+
CYP2E1
ROS
TCA cycle acetyl-CoA used
Microsome
in ketogenesis ( ketoacidosis),
Fomepizole Disulfiram lipogenesis ( hepatosteatosis).
– – Females are more susceptible than
Alcohol dehydrogenase Acetaldehyde dehydrogenase males to effects of alcohol due
Ethanol Acetaldehyde Acetate
to  activity of gastric alcohol
NAD+ NADH NAD+ NADH
Cytosol
Mitochondria dehydrogenase,  body size,
 percentage of water in body
weight.
Catalase NAD+ is the limiting reagent.
H2O2 H2O Peroxisome Alcohol dehydrogenase operates via
zero-order kinetics.
Ethanol metabolism NADH/
Gluconeogenesis Glycolysis NAD+ ratio in liver, causing:
Glucose
NADH NAD+ Lactic acidosis— pyruvate
conversion to lactate
Glyceraldehyde-3-P DHAP ↑ Glycerol-3-P
4A Fasting hypoglycemia—
gluconeogenesis due to
PEP
(fasting NADH NAD+ conversion of OAA to malate
hypoglycemia)
Pyruvate ↑ Lactate ↑ Triglycerides
Ketoacidosis—diversion of
Q (anion gap metabolic acidosis)
(hepatic acetyl-CoA into ketogenesis
steatosis) rather than TCA cycle
↑ Ketoacids
S Hepatosteatosis— conversion
Ketogenesis
↑
OAA Acetyl-CoA of DHAP to glycerol-3-P
4A ; acetyl-CoA diverges into
4B
NADH ↑ Fatty acids fatty acid synthesis 4B , which
R
OAA Isocitrate NAD+ Lipogenesis combines with glycerol-3-P to
synthesize triglycerides
NADH Fomepizole—competitive inhibitor
NAD+
TCA cycle of alcohol dehydrogenase;
↑ Malate α-KG
Pathways stimulated by ↑ NADH/NAD+ ratio preferred antidote for overdoses
NAD+
Pathways inhibited by ↑ NADH/NAD+ ratio of methanol or ethylene glycol.
Succinyl-
Alcohol dehydrogenase has
CoA NADH higher affinity for ethanol
than for methanol or ethylene
glycol ethanol can be used as
competitive inhibitor of alcohol
dehydrogenase to treat methanol
or ethylene glycol poisoning.
Disulfiram—blocks acetaldehyde
dehydrogenase acetaldehyde
hangover symptoms
discouraging drinking.

Biochemistry 
BIOCHEMISTRY—Metabolism SEC TION II 71
BIOCHEMISTRY—METABOLISM
`
Enzyme terminology An enzyme’s name often describes its function. For example, glucokinase is an enzyme that
catalyzes the phosphorylation of glucose using a molecule of ATP. The following are commonly
used enzyme descriptors.
Kinase Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate
(eg, phosphofructokinase).
Phosphorylase Adds inorganic phosphate onto substrate without using ATP (eg, glycogen phosphorylase).
Phosphatase Removes phosphate group from substrate (eg, fructose-1,6-bisphosphatase 1).
Dehydrogenase Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase).
Hydroxylase Adds hydroxyl group (−OH) onto substrate (eg, tyrosine hydroxylase).
Carboxylase Transfers carboxyl groups (−COOH) with the help of biotin (eg, pyruvate carboxylase).
Mutase Relocates a functional group within a molecule (eg, vitamin B12–dependent methylmalonyl-CoA
mutase).
Synthase/synthetase Joins two molecules together using a source of energy (eg, ATP, acetyl-CoA, nucleotide sugar).
Rate-determining enzymes of metabolic processes

PROCESS ENZYME REGULATORS
Glycolysis Phosphofructokinase-1 (PFK-1) AMP ⊕, fructose-2,6-bisphosphate ⊕
ATP ⊝, citrate ⊝
Gluconeogenesis Fructose-1,6-bisphosphatase 1 AMP ⊝, fructose-2,6-bisphosphate ⊝
TCA cycle Isocitrate dehydrogenase ADP ⊕
ATP ⊝, NADH ⊝
Glycogenesis Glycogen synthase Glucose-6-phosphate ⊕, insulin ⊕, cortisol ⊕
Epinephrine ⊝, glucagon ⊝
Glycogenolysis Glycogen phosphorylase Epinephrine ⊕, glucagon ⊕, AMP ⊕
Glucose-6-phosphate ⊝, insulin ⊝, ATP ⊝
HMP shunt Glucose-6-phosphate dehydrogenase (G6PD) NADP+ ⊕
NADPH ⊝
De novo pyrimidine Carbamoyl phosphate synthetase II ATP ⊕, PRPP ⊕
synthesis UTP ⊝
De novo purine Glutamine-phosphoribosylpyrophosphate AMP ⊝, inosine monophosphate (IMP) ⊝,
synthesis (PRPP) amidotransferase GMP ⊝
Urea cycle Carbamoyl phosphate synthetase I N-acetylglutamate ⊕
Fatty acid synthesis Acetyl-CoA carboxylase (ACC) Insulin ⊕, citrate ⊕
Glucagon ⊝, palmitoyl-CoA ⊝
Fatty acid oxidation Carnitine acyltransferase I Malonyl-CoA ⊝
Ketogenesis HMG-CoA synthase (HOMG! I’m starving!)
Cholesterol synthesis HMG-CoA reductase Insulin ⊕, thyroxine ⊕, estrogen ⊕
Glucagon ⊝, cholesterol ⊝

BIOCHEMISTRY—Metabolism
Metabolism sites
Mitochondria Fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation,
ketogenesis.
Cytoplasm Glycolysis, HMP shunt, and synthesis of cholesterol (SER), proteins (ribosomes, RER), fatty acids,
and nucleotides.
Both Heme synthesis, urea cycle, gluconeogenesis. Hugs take two (both).
Summary of pathways
Galactokinase (mild galactosemia) Galactose metabolism

Galactose-1-phosphate Galactose B Requires biotin cofactor
uridyltransferase
(severe galactosemia) T Requires thiamine cofactor (TPP)
Glycolysis # Irreversible, important point of regulation
Hexokinase/glucokinase Galactose-1-phosphate Glucose
Glycogen
Glucose-6-phosphatase HMP shunt
(von Gierke disease)
UDP-glucose Glucose-1-phosphate Glucose-6-phosphate 6-phosphogluconolactone
Glucose-6-phosphate
dehydrogenase Glycogenesis / glycogenolysis
Transketolase Fructose-6-phosphate Ribulose-5-phosphate
T
Phosphofructokinase-1 Gluconeogenesis
Fructose-1,6-bisphosphatase 1 Fructose-1,6-bisphosphate Fructose metabolism
Fructokinase (essential fructosuria)
Aldolase B (fructose intolerance) Glyceraldehyde-3-P DHAP Fructose-1-phosphate Fructose
Aldolase B (liver), A (muscle)
Triose phosphate isomerase 1,3-bisphosphoglycerate Glyceraldehyde
Pyruvate kinase
3-phosphoglycerate Glycerol Lipid metabolism
Pyruvate dehydrogenase
Pyruvate carboxylase
2-phosphoglycerate Triglycerides
PEP carboxykinase
Citrate synthase
Phosphoenolpyruvate (PEP) Fatty acids
Isocitrate dehydrogenase
α-ketoglutarate dehydrogenase Alanine Pyruvate Lactate Cholesterol
Malonyl-CoA
Carbamoyl phosphate synthetase I T
B
Ornithine transcarbamylase B Acetyl-CoA Mevalonate
Propionyl-CoA carboxylase Acetoacetyl-CoA HMG-CoA
HMG-CoA reductase
Citrate Acetoacetate
Oxaloacetate
NH3 + CO2 Aspartate
Citrulline Isocitrate β-hydroxybutyrate
Carbamoyl phosphate Argininosuccinate

Ketogenesis
Malate TCA cycle
Ornithine Odd-chain fatty acids,
Urea cycle α-ketoglutarate isoleucine, valine, methionine,
Fumarate threonine, pyrimidines
T
Arginine
Succinate Succinyl-CoA Methylmalonyl-CoA Propionyl-CoA
Urea B12 B
H2O Protein metabolism

Biochemistry 
Activated carriers CARRIER MOLECULE CARRIED IN ACTIVATED FORM

ATP Phosphoryl groups
NADH, NADPH, FADH2 Electrons
CoA, lipoamide Acyl groups
Biotin CO2
Tetrahydrofolates 1-carbon units
S-adenosylmethionine (SAM) CH3 groups
TPP Aldehydes
Universal electron Nicotinamides (NAD+, NADP+ from vitamin B3) NADPH is a product of the HMP shunt.
acceptors and flavin nucleotides (FAD from vitamin B2). NADPH is used in:
NAD+ is generally used in catabolic processes to Anabolic processes
carry reducing equivalents away as NADH. Respiratory burst
NADPH is used in anabolic processes (eg, Cytochrome P-450 system
steroid and fatty acid synthesis) as a supply of Glutathione reductase
reducing equivalents.
Hexokinase vs Phosphorylation of glucose to yield glucose-6-phosphate is catalyzed by glucokinase in the liver and
glucokinase hexokinase in other tissues. Hexokinase sequesters glucose in tissues, where it is used even when
glucose concentrations are low. At high glucose concentrations, glucokinase helps to store glucose
in liver. Glucokinase deficiency is a cause of maturity onset diabetes of the young (MODY) and
gestational diabetes.
Hexokinase Glucokinase
Location Most tissues, except liver Liver, β cells of pancreas
and pancreatic β cells
Km Lower ( affinity) Higher ( affinity)
Vmax Lower ( capacity) Higher ( capacity)
Induced by insulin No Yes
Feedback inhibition by Glucose-6-phosphate Fructose-6-phosphate

Glycolysis regulation, Net glycolysis (cytoplasm):

key enzymes Glucose + 2 Pi + 2 ADP + 2 NAD+ 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O.
Equation not balanced chemically, and exact balanced equation depends on ionization state of
reactants and products.
REQUIRE ATP Glucose Glucose-6-P Glucose-6-P ⊝ hexokinase.
Hexokinase/glucokinase
Fructose-6-P ⊝ glucokinase.
Fructose-6-P
Phosphofructokinase-1
Fructose-1,6-BP AMP ⊕, fructose-2,6-bisphosphate ⊕.
(rate-limiting step)
ATP ⊝, citrate ⊝.
PRODUCE ATP 1,3-BPG 3-PG

Phosphoglycerate kinase
Phosphoenolpyruvate Pyruvate Fructose-1,6-bisphosphate ⊕.

Pyruvate kinase
ATP ⊝, alanine ⊝, glucagon ⊝.
Regulation by Fructose bisphosphatase-2 (FBPase-2) and phosphofructokinase-2 (PFK-2) are the same
fructose-2,6- bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A.
bisphosphate
FBPase-1
Gluconeogenesis Fructose-6-P Fructose-1,6-BP Glycolysis
PFK-1
FBPase-2 PFK-2
active in active in
fasting state fed state
Fructose-2,6-BP
Fasting state: glucagon cAMP protein FaBian the Peasant (FBP) has to work hard
kinase A FBPase-2, PFK-2, less when starving.
glycolysis, more gluconeogenesis.
Fed state: insulin cAMP protein Prince FredericK (PFK) works only when fed.
kinase A FBPase-2, PFK-2, more
glycolysis, less gluconeogenesis.
Pyruvate Mitochondrial enzyme complex linking The complex is similar to the α-ketoglutarate
dehydrogenase glycolysis and TCA cycle. Differentially dehydrogenase complex (same cofactors,
complex regulated in fed (active)/fasting (inactive) states. similar substrate and action), which converts
+
Reaction: pyruvate + NAD + CoA acetyl- α-ketoglutarate succinyl-CoA (TCA cycle).
CoA + CO2 + NADH.
Contains 3 enzymes requiring 5 cofactors: The lovely coenzymes for nerds.
1. Thiamine pyrophosphate (B1) Arsenic inhibits lipoic acid. Arsenic poisoning
2. Lipoic acid clinical findings: imagine a vampire (pigmentary
3. CoA (B5, pantothenic acid) skin changes, skin cancer), vomiting and having
4. FAD (B2, riboflavin) diarrhea, running away from a cutie (QT
5. NAD+ (B3, niacin) prolongation) with garlic breath.
+
Activated by: NAD /NADH ratio, ADP
Ca2+.

Biochemistry 
Pyruvate Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
dehydrogenase X-linked.
complex deficiency
FINDINGS Neurologic defects, lactic acidosis, serum alanine starting in infancy.
TREATMENT intake of ketogenic nutrients (eg, high fat content or lysine and leucine).
Pyruvate metabolism Functions of different pyruvate metabolic

pathways (and their associated cofactors):
Glucose A lanine aminotransferase (B6): alanine
carries amino groups to the liver from
muscle
Pyruvate Pyruvate carboxylase (B7): oxaloacetate
ALT can replenish TCA cycle or be used in
LDH
Alanine NADH gluconeogenesis
Cahill cycle Cytosol + H+ NAD+ Pyruvate dehydrogenase (B1, B2, B3, B5,
Lactate
Mitochondria Cori cycle lipoic acid): transition from glycolysis to
PC
the TCA cycle

PDH
NAD+
CO2 + ATP
Lactic acid dehydrogenase (B3): end of
CO2 anaerobic glycolysis (major pathway in
NADH RBCs, WBCs, kidney medulla, lens,
Oxaloacetate + H+
testes, and cornea)
Acetyl-CoA
TCA cycle
Pyruvate (3C) Also called Krebs cycle. Pyruvate acetyl-CoA
CO2 + NADH ATP produces 1 NADH, 1 CO2.
*
PDH Acetyl-CoA The TCA cycle produces 3 NADH, 1 FADH2,
NADH
2 CO2, 1 GTP per acetyl-CoA = 10 ATP/
Acetyl-CoA (2C)
ATP acetyl-CoA (2× everything per glucose). TCA
cycle reactions occur in the mitochondria.
e synthase
Oxalo- Citrat α-ketoglutarate dehydrogenase complex
NADH acetate * Citrate (6C)
(4C) cis-Aconitate requires the same cofactors as the pyruvate
Malate (4C) dehydrogenase complex (vitamins B1, B2, B3,
Isocitrate (6C)
B5, lipoic acid).
* CO2 + NADH
Isocitrate ATP
Citrate is Krebs’ starting substrate for making
Fumarate (4C)
dehydrogenase NADH oxaloacetate.
ADP
FADH2 α-KG (5C)
ase
en
Succinate (4C) * dr CO2 + NADH

og
hy
GTP + CoA G de
Succinyl- α-K Succinyl-CoA
CoA (4C) NADH
ATP
* Enzymes are irreversible

Electron transport NADH electrons are transferred to complex I. 1 NADH 2.5 ATP; 1 FADH2 1.5 ATP
chain and oxidative FADH2 electrons are transferred to complex II NADH electrons from glycolysis enter
phosphorylation (at a lower energy level than NADH). mitochondria via the malate-aspartate or
The passage of electrons results in the formation glycerol-3-phosphate shuttle.
of a proton gradient that, coupled to oxidative Aerobic metabolism of one glucose molecule
phosphorylation, drives ATP production. ATP produces 32 net ATP via malate-aspartate
hydrolysis can be coupled to energetically shuttle (heart and liver), 30 net ATP via
unfavorable reactions. glycerol-3-phosphate shuttle (muscle).
Uncoupling proteins (found in brown fat, which Anaerobic glycolysis produces only 2 net ATP
has more mitochondria than white fat) produce per glucose molecule.
heat by inner mitochondrial membrane Aspirin overdose can also cause uncoupling
permeability proton gradient. ATP synthesis of oxidative phosphorylation resulting in
stops, but electron transport continues. hyperthermia.
ADP + Pi ATP
NADH NAD+ FADH2 FAD 1/2 O2 + 2H+ H2O Mitochondrial
matrix
Inner mitochondrial
CoQ membrane
Cyto-
chrome c
Complex I Complex II Complex III Complex IV Complex V Intermembrane
(succinate space
dehydrogenase)
Uncoupling proteins Cyanide,

H+ H+ CO H+ H+
Aspirin overdose
Gluconeogenesis, All enzymes may be subject to activation by Pathway produces fresh glucose.
irreversible enzymes glucagon in fasting state.
Pyruvate carboxylase In mitochondria. Pyruvate oxaloacetate. Requires biotin, ATP. Activated by acetyl-CoA.
Phosphoenolpyruvate In cytosol. Oxaloacetate Requires GTP.
carboxykinase phosphoenolpyruvate (PEP).
Fructose-1,6- In cytosol. Fructose-1,6-bisphosphate Citrate ⊕, AMP ⊝, fructose 2,6-bisphosphate ⊝.
bisphosphatase 1 fructose-6-phosphate.
Glucose-6- In ER. Glucose-6-phosphate glucose.
phosphatase
Occurs primarily in liver; serves to maintain euglycemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
(Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase).
Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle
(as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source (It’s odd for fatty acids
to make glucose). Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-
CoA equivalents.

Biochemistry 
Pentose phosphate Also called HMP shunt. Provides a source of NADPH from abundantly available glucose-6-P
pathway (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, fatty acid
and cholesterol biosynthesis). Additionally, this pathway yields ribose for nucleotide synthesis. Two
distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is
used or produced.
Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs.
REACTIONS
Oxidative NADP+ NADPH NADP+ NADPH CO2
(irreversible) Glucose-6-Pi 6-Phosphogluconate Ribulose-5-Pi
Glucose-6-P dehydrogenase
Nonoxidative Phosphopentose
isomerase
(reversible)
Fructose-6-Pi Ribose-5-Pi
Transketolase, B₁
Fructose Nucleotide
1,6-bisphosphate synthesis
DHAP Glyceraldehyde-3-Pi
Glucose-6-phosphate NADPH is necessary to keep glutathione X-linked recessive disorder; most common
dehydrogenase reduced, which in turn detoxifies free radicals human enzyme deficiency; more prevalent
deficiency and peroxides. NADPH in RBCs leads to among descendants of populations in malaria-
hemolytic anemia due to poor RBC defense endemic regions (eg, sub-Saharan Africa,
against oxidizing agents (eg, fava beans, Southeast Asia).
sulfonamides, nitrofurantoin, primaquine). Heinz bodies—denatured globin chains
Infection (most common cause) can also precipitate within RBCs due to oxidative stress.
precipitate hemolysis; inflammatory response Bite cells—result from the phagocytic removal
produces free radicals that diffuse into RBCs, of Heinz bodies by splenic macrophages.
causing oxidative damage. Think, “Bite into some Heinz ketchup.”
Glucose-6-P NADP+ 2 GSH H2O2
(reduced)
Glucose-6-P Glutathione Glutathione

dehydrogenase reductase peroxidase
6-phosphogluconolactone NADPH GSSG 2H2O

(oxidized)

Disorders of fructose metabolism

Essential fructosuria Hereditary fructose intolerance
ENZYME DEFICIENCY Fructokinase (autosomal recessive) Aldolase B (autosomal recessive)
PATHOPHYSIOLOGY Fructose is not trapped into cells. Hexokinase Fructose-1-phosphate accumulates available
becomes 1° pathway for converting fructose to phosphate inhibition of glycogenolysis and
fructose-6-phosphate. gluconeogenesis.
PRESENTATION (SIGNS/SYMPTOMS) Asymptomatic, benign. Fructose appears in Hypoglycemia, jaundice, cirrhosis, vomiting.
blood and urine (fructokinase deficiency is Symptoms only present following consumption
kinder). of fruit, juice, or honey.
ADDITIONAL REMARKS Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine
(nonspecific test for inborn errors of carbohydrate metabolism).
TREATMENT – intake of fructose, sucrose (glucose + fructose),
and sorbitol (metabolized to fructose).
Triose phosphate
isomerase
Dihydroxyacetone-P
Fructokinase Aldolase B
Fructose Fructose-1-P se Glyceraldehyde-3-P Glycolysis
se kina
Trio
ATP ADP Glyceraldehyde
ADP
ATP
NADH
NAD+
Glycerol
Disorders of galactose metabolism

Galactokinase deficiency Classic galactosemia
ENZYME DEFICIENCY Galactokinase (autosomal recessive). Galactose-1-phosphate uridyltransferase
(autosomal recessive).
PATHOPHYSIOLOGY Galactitol accumulates if diet has galactose. Damage caused by accumulation of toxic
substances (eg, galacitol).
PRESENTATION (SIGNS/SYMPTOMS) Relatively mild/benign condition (galactokinase Symptoms start when infant is fed formula
deficiency is kinder). or breast milk failure to thrive, jaundice,
Galactose appears in blood (galactosemia) and hepatomegaly, infantile cataracts (galacitol
urine (galactosuria); infantile cataracts. May deposition in eye lens), intellectual disability.
present as failure to track objects or develop Can predispose neonates to E coli sepsis.
social smile.
TREATMENT – Exclude galactose and lactose (galactose +
glucose) from diet.
Galactokinase Uridylyltransferase
Galactose Galactose-1-P Glucose-1-P
ATP
ADP
UDP-Glu UDP-Gal
Aldose
reductase
4-Epimerase Glycolysis/glycogenesis
Galactitol

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www.medicalstudyzone.

CONNIE QIU, MD, PhD ANUP CHALISE, MBBS, MS, MRCSEd

PANAGIOTIS KAPARALIOTIS, MD CAROLINE COLEMAN, MD

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Contributing Authors vii General Acknowledgments xiii

Introduction 2 Test-Taking Strategies 19

How to Use the Database 28 Pathology 201

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How to Use the Database 742 Biochemistry 746

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Selected USMLE Laboratory Values

* = Included in the Biochemical Profile (SMA-12)

Blood, Plasma, Serum Reference Range SI Reference Intervals

*Alanine aminotransferase (ALT, GPT at 30°C) 10–40 U/L 10–40 U/L

Bicarbonate (HCO3–) 22–28 mEq/L 22–28 mmol/L

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Cerebrospinal Fluid Reference Range SI Reference Intervals

Cell count 0–5/mm3 0–5 × 106/L

Erythrocyte count Male: 4.3–5.9 million/mm3 4.3–5.9 × 1012/L

Creatinine clearance Male: 97–137 mL/min 97–137 mL/min

Body mass index Adult: 19–25 kg/m2 19–25 kg/m2

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Months Prior Review computer test format and registration information.

Weeks Prior Do test simulations in question banks.

One Day Prior Relax.

Day of Exam Relax.

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“One important key to success is self-confidence. An important key to self- ` Introduction2

“It always seems impossible until it’s done.” ` Testing Agencies 22

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 Starting to study (including First Aid) too late

USMLE STEP 1—THE BASICS

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How Is the Computer-Based Test (CBT) Structured?

The CBT Step 1 exam consists of one “optional” tutorial/simulation block

Once an examinee finishes a particular question block on the CBT, he or

What Is the CBT Like?

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` Familiarize yourself with the commonly

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You may register for a practice session online at www.usmle.org. A separate

How Do I Register to Take the Exam?

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What If I Need to Reschedule the Exam?

When Should I Register for the Exam?

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How Long Will I Have to Wait Before I Get My Result?

What About Time?

15 minutes Tutorial (skip if familiar with test format and features)

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If I Freak Out and Leave, What Happens to My Exam?

What Types of Questions Are Asked?

` Nearly three fourths of Step 1 questions begin

T A B L E 2 . Passing Rates for the 2020-2021 USMLE Step 1.2

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How Is the Test Scored?

Official NBME/USMLE Resources

The NBME offers a Comprehensive Basic Science Examination (CBSE) for

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The CBSSA exists in two formats: standard-paced and self-paced, both of

Lastly, the International Foundations of Medicine (IFOM) offers a Basic

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T A B L E 3 . Effective Learning Strategies.

“One important key to success is self-confidence. An important key to self- ` Introduction2

“It always seems impossible until it’s done.” ` Testing Agencies 22

Starting to study (including First Aid) too late

15 minutes Tutorial (skip if familiar with test format and features)

National Board of Medical Examiners (NBME) / USMLE Secretariat

Educational Commission for Foreign Medical Graduates (ECFMG)

Hydroxyurea AMP GMP Mycophenolate and ribavirin: inhibit inosine

5-FU Methotrexate (MTX), trimethoprim (TMP),