LANGE Biochemistry And Genetics

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 Lange® Flashcards:
Biochemistry & Genetics
Third Edition
Series Editors
Suzanne J. Baron, MD, MSc Christoph I. Lee, MD, MS
St. Luke’s Mid America Heart Institute University of Washington School of Medicine
Kansas City, Missouri Seattle, Washington
Student Editor
Alexander H. Sun
Yale University School of Medicine
New Haven, Connecticut

New York / Chicago / San Francisco / Athens / London / Madrid

Mexico City / Milan / New Delhi / Singapore / Sydney / Toronto

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 Notice

Medicine is an ever-changing science. As new research and clinical experience broaden our knowl-
edge, changes in treatment and drug therapy are required. The authors and the publisher of this work
have checked with sources believed to be reliable in their efforts to provide information that is com-
plete and generally in accord with the standards accepted at the time of publication. However, in view
of the possibility of human error or changes in medical sciences, neither the authors nor the publisher
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the information contained herein is in every respect accurate or complete, and they disclaim all respon-
sibility for any errors or omissions or for the results obtained from use of the information contained
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tions for administration. This recommendation is of particular importance in connection with new or
infrequently used drugs.

FM.indd 2 14-08-2017 17:51:18

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 Contents

Preface vii
Acknowledgments ix
About the Authors xi
Abbreviations xiii

1 Cellular Energy 1–4

2 Carbohydrate Metabolism 5-27
3 Lipid Metabolism 28-58
4 Amino Acid Metabolism 59-75
5 Nucleotide Metabolism 76-85
6 Heme Metabolism 86-94
7 Steroid Hormone Synthesis 95-102
8 Nutrition 103-121
9 Cellular Biology and Genetics 122-196

References 197
Index 198

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 Preface

When we began to review the biochemistry and genetics material covered in the USMLE Step 1 at the end of
our second year at Yale Medical School, we realized that most of the practice questions were approaching the
material from a clinical perspective and not from the basic science perspective in which we had learned these
topics. Although we had taken introductory biochemistry and genetics courses back in college and covered
the material again during the first few months of medical school, we found ourselves studying the clinical
aspects of biochemical and genetic diseases for the first time. Flipping through the highly rated biochemistry
and genetics review sources, we realized that there was no gold standard review source for these high-yield
topics that make up 15% of USMLE Step 1 questions.
Lange® Flashcards: Biochemistry & Genetics is the result of our struggles in studying these topics for
Step 1 with the clinical slant that the boards demand. These cards offer the most complete, concise, and
high-yield information for the major biochemical and genetic diseases tested on Step 1 and in medical school
basic science courses. We are confident that the content covered in the third version of our cards includes
the most current and board-relevant information that cannot be found in any other single biochemistry and
genetics review text. We added a current medical student editor to help ensure that the content is up-to-date
and boards relevant.
We are pleased to present this information in a format modeled after Lange® Flashcards: Pathology, our
first publication in this series. Each card provides a structured presentation of a specific disease and allows
students to easily compare and contrast diseases. The introductory cards in each chapter describe the basic

vii

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 principles of biochemistry and genetics that are board relevant and high yield. Each disease-specific card
contains a clinical vignette on one side and important characteristics on the reverse side. These characteristics
are organized into sections entitled biochemical or genetic defect, pathophysiology, clinical manifestations,
treatment, and additional pearls. The most salient features of each disease are highlighted in bold for ease of
rapid review.
We suggest using these cards as an adjunct to your biochemistry and genetics courses in medical school.
Being familiar with these cards early on will be very helpful during your Step 1 review. We also encourage
you to jot down your own notes in the margins and to make these cards your personal biochemistry and genet-
ics review for the boards.
We are confident that the newly revised third edition of Lange® Flashcards: Biochemistry & Genetics
will be one of the most powerful tools to help prepare you for the boards and will serve as a resource that will
bridge your basic science knowledge with the clinical aspects of disease. We wish you the best of luck on
Step 1 and welcome your comments on how to improve this study tool in the next edition.
Suzanne J. Baron
suzanne.baron@gmail.com
Christoph I. Lee
stophlee@gmail.com

viii

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 Acknowledgments

We would like to thank the many editors at McGraw-Hill for all of their support and hard work on this project
as well as their constant encouragement of the Lange® Flashcards series. A special thanks to Alexander Sun
for serving as a student editor for this revised edition. We also acknowledge the many basic and clinical sci-
ence teaching faculty of the Yale University School of Medicine who provided much of the foundation for
the relevant content in these cards.
To our family and friends, we thank you for your continuing support and love that have made this process
even more meaningful. Special thanks to John and Jay Lee, Fran and Joe Baron, Paul B. Brennan III, Monique
Mogensen, Bettina Lee, and Elena Lee.

ix

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 About the Authors

Suzanne J. Baron MD, MSc, earned an AB magna cum laude in psychology and biology from Harvard
University, her MD from Yale University School of Medicine, and her MSc from Harvard School of Public
Health. She completed her internal medicine residency, cardiology fellowship, and interventional cardiology
fellowship at Massachusetts General Hospital. She is currently practicing at St. Luke’s Mid America Heart
Institute in Kansas City, Missouri, as an interventional cardiologist with an interest in structural heart disease.
Dr. Baron is also involved in outcomes research aimed at evaluating the effects of cardiac devices on quality
of life and health economics and her research has been published in several peer-reviewed journals, including
JAMA and JACC.

Christoph I. Lee, MD, MS, earned an AB cum laude in English from Princeton University, an MD cum laude
from Yale University, and an MS in health policy and management research from UCLA. He completed his
diagnostic radiology residency at Stanford University, a breast imaging fellowship at UCLA, and a national
health policy fellowship as a Robert Wood Johnson Foundation Clinical Scholar. He is currently an associ-
ate professor of radiology and health services at the University of Washington. Dr. Lee is the author of five
medical books spanning the basic sciences, evidenced-based practice, and medical imaging. He has obtained
extramural research funding from the National Institutes of Health, American Cancer Society, and Agency
for Healthcare Research and Quality for imaging-related outcomes research, and has published more than 60
peer-reviewed journal articles.

xi

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 Abbreviations
1,2-DAG: 1,2-diacylglycerol
2,3-BPG: 2,3-bisphosphoglycerate
α-t: α-thalassemias
β-t: β-thalassemias
ABG: arterial blood gas
AC: adenylate cyclase
ACE: angiotensin-converting-enzyme
ACTH: adrenocorticotropic hormone
ADA: adenosine deaminase
ADP: adenosine diphosphate
ALA: aminolevulinic acid
ALL: acute lymphoblastic leukemia
ALT: alanine aminotransferase
AMP: adenosine monophosphate
Apo: apoprotein
ATP: adenosine triphosphate
AST: aspartate aminotransferase
ATP: adenosine triphosphate
AUG: adenine uracil guanine
xiii
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BAL: British anti-Lewisite, dimercaprol
BCKD: branched-chain α-ketoacid dehydrogenase
BSS: Bernard-Soulier syndrome
Btk: Bruton tyrosine kinase
BUN: blood urea nitrogen
CAG: cytosine adenine guanine
cAMP: cyclic adenosine monophosphate
CBC: complete blood count
CDP: cytidine diphosphate
CFTR: cystic fibrosis transmembrane conductor
regulator
CGG: cytosine guanine guanine
CHF: congestive heart failure
Chr: chromosome
Cl−: chloride ion
CMT: Charcot-Marie-Tooth (disease)
CNS: central nervous system
CoA: coenzyme A
COPRO: coproporphyrinogen
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 CT: computed tomography
CTG: cytosine thymidine guanine
CTP: cytosine-5′-triphosphate
dADP: deoxyadenosine diphosphate
dATP: deoxyadenosine triphosphate
dCDP: deoxycytidine diphosphate
dGDP: deoxyguanosine diphosphate
DHEA: dehydroepiandrosterone
DHT: dihydrotestosterone
DMD: Duchenne muscular dystrophy
DNA: deoxyribonucleic acid
DNAO: DNA polymerase
DNAP: DNA polymerase
DOPA: dihydroxyphenylalanine
dTMP: deoxythymidylate
DTRs: deep tendon reflexes
dUDP: deoxyuridine 5′-diphosphate
dUMP: deoxyuridylate
ECG: electrocardiogram
EDS: Ehlers-Danlos syndrome
ESR: erythrocyte sedimentation rate
xiv
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ESRD: end-stage renal disease
F1,6BP: fructose 1,6 bisphosphate
F6P: fructose-6-phosphate
FAD: flavin adenine dinucleotide
FAMN: flavin adenine mononucleotide
FEP: free erythrocyte protoporphyrin
FEV1: forced expiratory volume in 1 second
FGFR3: fibroblast growth factor receptor 3
FMN: flavin mononucleotide
FMR-1: familial mental retardation
FSH: follicle-stimulating hormone
FVC: functional vital capacity
G3P: glyceraldehyde-3-phosphate
G6P: glucose-6-phosphate
G6PD: glucose-6-phosphate dehydrogenase
GAA: guanine adenine adenine
GAG: glycosaminoglycan
G-CSF: granulocyte colony–stimulating factor
FGFR3: fibroblast growth factor receptor 3
GDP: guanosine diphosphate
GFR: glomerular filtration rate
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 GI: gastrointestinal
GMP: guanosine monophosphate
GT: Glanzmann thrombasthenia
GTP: guanosine triphosphate
HD: Huntington disease
HDL: high-density lipoprotein
Hgb: hemoglobin
HGPRT: hypoxanthine-guanine
phosphoribosyltransferase
HIV: human immunodeficiency virus
HMG-CoA: 5-hydroxy-3-methylglutaryl
coenzyme A
HMP: hexose monophosphate
IBD: inflammatory bowel disease
IDL: intermediate-density lipoprotein
IMP: inosine monophosphate
IV: intravenous
IVP: intravenous pyelogram
KUB: kidneys, ureter, bladder (x-ray)
LDL: low-density lipoprotein
xv
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LFTs: liver function tests
LH: luteinizing hormone
LHON: Leber hereditary optic neuropathy
LPL: low-density lipoprotein
MCHC: mean corpuscular hemoglobin
concentration
MCV: mean corpuscular volume
MELAS: mitochondrial encephalomyopathy with
lactic acidosis and strokelike episodes
MEN: multiple endocrine neoplasia
MERRF: myoclonic epilepsy with ragged red
fibers
MI: myocardial infarction
MRI: magnetic resonance imaging
mRNA: messenger RNA
mtDNA: mitochondrial DNA
MTP: metatarsophalangeal
NAD: nicotinamide adenine dinucleotide
NADP: nicotinamide adenine dinucleotide
phosphate
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 NADPH: nicotinamide adenine dinucleotide RUQ: right upper quadrant
phosphate hydrogen SAM: S-adenosylmethionine
NF1: neurofibromatosis 1 SCID: severe combined immunodeficiency
NPD: Niemann-Pick disease SSB: single-strand DNA binding
NPTHM: N5-methyl tetrahydrofolate homocysteine TB: tuberculosis
methyltransferase TGF-β: tissue growth factor β
NSAID: nonsteroidal anti-inflammatory drug TIBC: total iron-binding capacity
OMP: orotidine-5′-monophosphate TLC: total lung capacity
PBG: porphobilinogen TMP-SMX: trimethoprim-sulfamethoxazole
PPD: purified protein derivative TPP: thiamine pyrophosphate
PRPP: phosphoribosylpyrophosphate TTP: thymidine triphosphate
PT: prothrombin time tRNA: transfer ribonucleic acid
PTH: parathyroid hormone UA: urinalysis
PTT: partial thromboplastin time UDP: uridine 5′-diphosphate
RBC: red blood cell UDPGT: uridine diphosphoglucuronosyl
RFLP: restriction fragment length transferase
polymorphism UMP: uridine-5′-monophosphate
RNA: ribonucleic acid URO: uroporphyrinogen
RNAP: RNA polymerase UTI: urinary tract infection
rRNA: ribosomal ribonucleic acid UTP: uracil-5′-triphosphate

xvi

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 UV: ultraviolet vWF: von Willebrand factor
VLDL: very-low-density lipoprotein WAS: Wiskott-Aldrich syndrome
VMA: vanillylmandelic acid XR: x-ray

xvii

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 CELLULAR ENERGY

GENERAL CONCEPTS

Citric acid cycle

Electron transport chain
NADH shuttles

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 CITRIC ACID CYCLE

1
Acetyl CoA
Citrate Synthase
NADH Oxaloacetate Citrate
Ac
NAD+ on
ita
te ase se
ala n
M roge
y d
Malate Deh Isocitrate
NAD+

Dehydrogenase
Isocitrate
NADH
Fumarase

CO2

Fumarate α-ketoglutarate
te
De Suc ara
hy cin lut ase
dr at
og e e tog ogen NAD+
K
en
as α- hydr
FADH2 e
De
NADH
FAD Succinate Succinyl CoA CO2
Succinyl CoA Synthase

GTP GDP

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 CITRIC ACID CYCLE

The citric acid cycle occurs in the mitochondrial matrix. Functions include the oxidation of acetyl CoA to
CO2, the formation of NADH and FADH2 for entrance into the electron transport chain and subsequent ATP
generation, and the synthesis of several important molecules, including succinyl CoA (precursor molecule of
heme), oxaloacetate (early intermediate molecule in gluconeogenesis and substrate for amino acid synthesis),
α-ketoglutarate (substrate for amino acid synthesis), and citrate (substrate for fatty acid synthesis).

YIELD OF THE CITRIC ACID CYCLE REGULATION OF THE CITRIC ACID CYCLE

Each molecule of acetyl CoA entering the citric acid Enzyme Inhibitors Activators
cycle yields the following:
Citrate synthase ATP ADP
• Two CO2 NADH
• Three NADH Succinyl CoA
• One FADH2 Citrate

• One GTP Isocitrate ATP ADP

­dehydrogenase NADH
Because each NADH will eventually produce 2.5
α-Ketoglutarate ATP or GTP —
ATP and each FADH2 will produce 1.5 ATP through dehydrogenase NADH
the electron transport chain, the overall ATP yield (requires B1, B2, B3, Succinyl CoA
from 1 acetyl CoA is 10 ATP (7.5 from NADH, 1.5 CoA, and lipoic acid)
from FADH2, and 1 from GTP).
2

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 ELECTRON TRANSPORT CHAIN

Intermembrane Space
+
H+ H
H+
H+ H+ H+
+ H+
H H+
H+ H+ H+

e– e–
e–
I CoQ III IV V
CC e–
II
NADH
e– H2O
FADH2
ADP
NAD+ 1/2O2
FAD
ATP
H+ H+ H+
Mitochondrial Matrix

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 ELECTRON TRANSPORT CHAIN
COMPONENTS OF THE ELECTRON
TRANSPORT CHAIN
Complex I (NADH dehydrogenase): Contains FMN, which
accepts 2 e− and H+ from 2 NADH to become the reduced
form of FMNH2; also contains iron atoms, which assist in the
transfer of the e− and H+ to coenzyme Q. Inhibited by amobar-
bital and rotenone (found in pesticides).
Complex II (succinate dehydrogenase): Contains iron and suc-
cinate, which oxidizes FAD to form FADH2. Inhibited by anti-
mycin A.
Coenzyme Q: Accepts e− from FMNH2 (complex I) and
FADH2 (complex II). Transfers e− to complex III.
Complex III (cytochrome b): Contains heme group, in which
the Fe3+ accepts the e− from coenzyme Q to become Fe2+.
Transfers e− to cytochrome c. Inhibited by antimycin A (which
binds to cytochrome c reductase, thereby preventing transfer of
e− from cytochrome b to cytochrome c).
Cytochrome c: Contains heme group, in which the Fe3+
accepts the e− from complex III to become Fe2+. Transfers e− to
complex IV.
3
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Complex IV (cytochrome a): Contains heme group, in which
the Fe3+ accepts e− from cytochrome c to become Fe2+.
Transfers e− to O2, which is combined with hydrogen to form
H2O. Inhibited by cyanide (binds Fe3+ moiety on complex IV
and prevents the transfer of e− O2), CO, and sodium azide.
Complex V (ATP synthase): Contains a proton channel that allows
protons to cross into the matrix, using the proton gradient energy
to form ATP. Inhibited by oligomycin (blocks H+ channel).
Each NADH yields 2.5 ATP; each FADH2 yields 1.5 ATP.
THE CHEMIOSMOTIC HYPOTHESIS
Electron transport causes H+ ions to be pumped from the mito-
chondrial matrix into the intermembrane space, thereby result-
ing in the formation of an electrical and pH gradient across the
inner mitochondrial membrane. The energy created by the for-
mation of this gradient is then harnessed to form ATP as the
protons travel down their gradient into the matrix through ATP
synthase channel (complex V). 2, 4-dinitrophenol and aspirin
act to make the membrane more permeable, which results in
dissipation of the proton gradient and subsequent uncoupling of
ATP formation from electron transport.
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 SHUTTLING CYTOPLASMIC NADH INTO THE MITOCHONDRIA TO THE ETC

1
Malate shuttle: Oxaloacetate accepts electrons from NADH to become malate. Malate then enters the
mitochondria, where it is oxidized to form NADH and oxaloacetate. This shuttle produces a net gain of 32
ATP per molecule of glucose metabolized.

Cytoplasm NADH NAD+

Aspartate Oxaloacetate Malate

Inner Mitochondrial Membrane

Aspartate Oxaloacetate Malate

NADH NAD+
Mitochondrial Matrix
4

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 SHUTTLING CYTOPLASMIC NADH INTO THE MITOCHONDRIA TO THE ETC

α-Glycerol phosphate shuttle: DHAP accepts electrons from NADH to become α-Glycerol phosphate.
α-Glycerol phosphate enters the mitochondria, where it is oxidized to form FADH2 and DHAP. Here, only
1.5 ATPs are formed for each cytoplasmic NADH oxidized since FADH2 is produced. This shuttle produces a
net gain of 30 ATP per molecule of glucose metabolized.
Cytoplasm
NADH NAD+

Dihydroxyacetone-P α-Glycerol-P

Inner Mitochondrial Membrane

Dihydroxyacetone-P α-Glycerol-P

FADH2 FAD+
Mitochondrial Matrix
4

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 CARBOHYDRATE METABOLISM

GENERAL CONCEPTS DISEASES

Glycogenesis Glycogen Storage Diseases 2

Glycogenolysis Von Gierke disease
Glycolysis Pompe disease
Regulation of gluconeogenesis and glycolysis by fructose-2,6-bisphosphate Cori disease
Glucokinase vs. hexokinase McArdle disease
Pyruvate metabolism Liver phosphorylase deficiency
Pentose phosphate pathway Andersen disease
Fructose metabolism Tarui disease
Polyol pathway Pyruvate Dehydrogenase Complex Deficiency
Galactose metabolism Glucose-6-Phosphate Dehydrogenase Deficiency
Lactose metabolism Disorders of Fructose Metabolism
Gluconeogenesis Essential fructosuria
Cori cycle Fructose intolerance
Disorders of Galactose Metabolism
Classic galactosemia
Galactokinase deficiency
Disorders of Lactose Metabolism
Lactase deficiency

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 GLYCOGENESIS

O O O • Location: Glycogenesis takes place in the cyto-

+ plasm of cells in muscle, liver, and adipose tissue.
O OH UDP OH 2
• Substrate: UDP-glucose.
UDP-Glucose
Glycogen • Enzymes: Glycogen synthase adds glucose
Synthase
UDP
units to the nonreducing ends of existing chains
in α-1,4 linkages. Glucosyl (4:6) transferase
O O O
(also known as branching enzyme) transfers
O O O
+ seven-glucose-residue-long pieces from the
O O O O
OH OH nonreducing ends of the chains to create inter-
-1,4-glycosidic
Glucosyl (4:6) nal branches with α-1,6 linkages.
Transferase
bond • Stimulator: Insulin stimulates glycogenesis
via dephosphorylation and thus activation of
O O
glycogen synthase and inhibition of glycogen
O -1,6-glycosidic
bond
phosphorylase.
O O
O • Inhibitors: Glucagon (liver) and epinephrine
O O O (liver and muscle) inhibit glycogenesis via
O O
the cAMP protein kinase A phosphorylation
OH
cascade, which results in phosphorylation and
thus deactivation of glycogen synthase.
6

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 GLYCOGENOLYSIS

O O
• Location: Glycogenolysis takes place in the cytoplasm
Glycogen of cells in muscle, liver, and adipose tissue.
O • Substrate: Glucose-1-phosphate is released from the
O nonreducing ends of glycogen chains.
O O O • Enzymes: Glycogen phosphorylase breaks α-1,4
O O OH ­linkages and debranching enzyme breaks α-1,6 link-
ages to release single units of glucose-1-phosphate.
Debranching Phosphoglucomutase converts glucose-1-phosphate to
Enzyme
glucose-6-phosphate, which is then shuttled into the
O O O O O glycolytic pathway.
+ • Stimulators: Glucagon (liver) and epinephrine (via acti-
O O OH O OH vation of β-epinephrine receptors in the liver and muscle)
stimulate glycogenolysis via the cAMP protein kinase A
Ph
Gl pho
os
yc ry

phosphorylation cascade, which results in the phosphory-

og las
en e

lation and thus activation of glycogen phosphorylase.

O O Activation of α-epinephrine receptors by epinephrine
+ Glucose-1-Phosphate stimulates glycogenolysis via increased calcium levels,
O OH
Phosphoglucomutase which results in the activation of glycogen phosphory-
lasekinase. Glycogen phosphorylasekinase then acts to
Glucose-6-Phosphate Glycolysis phosphorylate and activate glycogen phosphorylase.
• Inhibitors: Insulin inhibits glycogenolysis via dephos-
phorylation and thus results in inactivation of glycogen
phosphorylase.

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 GLYCOLYSIS

Phase I

Hexokinase or Phosphohexose 2
Glucokinase Isomerase Phosphofructokinase 1
Glucose Glucose-6-Phosphate Fructose-6-Phosphate Fructose-1,6-Bisphosphate

ATP ATP
ADP ADP Aldolase
Triose Phosphate
Isomerase
Dihydroxyacetone Phosphate Glyceraldehyde-3-Phosphate
+
NAD
Phase II Glyceraldehyde-3-Phosphate
Dehydrogenase
NADH
Phosphoglycerate Phosphoglycerate Kinase
Mutase
2-Phosphoglycerate 3-Phosphoglycerate 1,3-Bisphosphoglycerate

Enolase ADP

ATP
Pyruvate Kinase
Phosphoenolpyruvate Pyruvate

ADP
ATP

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 GLYCOLYSIS

GENERAL INFORMATION REGULATION OF GLYCOLYSIS

• Location: Glycolysis takes place in the cytoplasm Enzyme Inhibitors Activators

of cells in most body tissues.
Hexokinase Glucose-6- Insulin
• Phase I: Energy investment phase.
phosphate
▶ Converts one glucose to two G3P.
Glucagon
▶ Consumes two ATP.
Glucokinase Fructose-6- Insulin
▶ Includes rate-limiting step of the conversion
phosphate
of fructose-6-phosphate to fructose-1,6- Glucagon
bisphosphonate as catalyzed by
Phosphofructo- Glucagon Fructose-2,
phosphofructokinase.
kinase (rate-limiting ATP 6-bisphophate
• Phase II: Energy production phase. enzyme) Citrate Insulin AMP
▶ Converts two G3P to two pyruvates.
Pyruvate kinase Glucagon Insulin
▶ Produces four ATP and two NADH.
ATP Fructose-1,
• Diseases: Deficiency in any of the glycolytic Alanine 6-bisphosphonate
enzymes leads to hemolytic anemia because
RBCs depend on glycolysis for energy produc-
tion and will lyse if their energy demands are not
met as a result of faulty glycolysis.

CH02.indd 7 11-08-2017 15:03:13

 REGULATION OF GLUCONEOGENESIS AND GLYCOLYSIS BY FRUCTOSE-2-6-BISPHOSPHATE

Fasting State Fed State

Pyruvate 2
Glucagon Insulin

+ +

Glycolysis
Fructose Phospho-
Fructose-1,6- Bisphosphatase-2 Fructose-2,6- Fructose-1,6- Fructokinase-2 Fructose-2,6-
Bisphosphate Bisphosphate Bisphosphate Bisphosphate
Fructose-1,6-Bisphosphatase
Phosphofructokinase-1

+
Gluconeogenesis

Fructose-6-Phosphate Glucagon Fructose-6-Phosphate

Low levels of F-2,6-BP
Insulin
Glycolytic High levels of F-2,6-BP
Enzymes

Glucose

• Purpose: Allows for up-regulation of gluconeogenesis when glucose levels are low (e.g. in fasting state) or for up-regulation of glycolysis when glucose
levels are high (e.g. in fed state).
• Description of regulatory mechanism
▶  Fructose bisphosphatase-2 (FBPase-2) and phosphofructokinase-2 (PFK-2) are two functions of a single enzyme, which controls the production of
fructose-2,6-bisphosphate (F-2,6-BP).
◦ High
 concentrations of F-2,6-BP activate phosphofructokinase-1 (PFK-1), thus promoting glycolysis. Low concentrations of F-2-6-BP activate
fructose-1-6-bisphosphatase (FBPase-1), thus promoting gluconeogenesis.
▶ Glucagon leads to the phosphorylation of the FBPase-2/PFK-2 enzyme with resulting activation of FBPase-2. Glucagon also stimulates FBPase-I.
▶ Insulin leads to the dephosphorylation of the FBPase-2/PFK-2 enzyme with resulting activation of PFK-2. Insulin also stimulates PFK-1.
8

CH02.indd 8 11-08-2017 15:03:15

 GLUCOKINASE VERSUS HEXOKINASE

Glucokinase Hexokinase
Location Liver and β cells of pancreas Most tissues
Substrate Glucose Many hexoses (e.g., glucose,
g­alactose, fructose)
Inhibited by glucose-6-phosphate No Yes
Affinity for glucose Low High
KM 10 mM 0.1 mM
VMax High Low
Inducibility Yes (in the liver by insulin) No
Product of reaction with glucose Glucose-6-phosphate Glucose-6-phosphate
Effect of glucose-6-phosphate None Allosteric inhibition
on enzyme activity
Function Acts to store glucose in the liver for Acts to isolate glucose inside cells for
conversion to glycogen utilization by organs
Clinical significance Gene mutation is associated with Deficiency leads to hemolytic anemia
Maturity-Onset Diabetes of the
Young (MODY)

CH02.indd 8 11-08-2017 15:03:15

 PYRUVATE METABOLISM

The Fates of Pyruvate

2

Cytosol Mitochondria

se Pyru
fera Pyruvate
notrans vate
Car
ine Ami boxy
lase
Alan
NADH

Pyru
genas
Glutamate H
+
+ CO2
NAD

vate
Alanine hydro Oxaloacetate
α−Ketoglutarate

Deh
te De

ydro
+
NAD
NADH
Lacta

gena
+
H

se
CO2

Lactate Acetyl CoA

CH02.indd 9 11-08-2017 15:03:15

 ENZYMES OF PYRUVATE METABOLISM

PYRUVATE DEHYDROGENASE ALANINE AMINOTRANSFERASE

• Location: Mitochondria • Location: Cytosol (higher levels seen in liver)

• Cofactors: Thiamine pyrophosphate; FAD; NAD+; • Cofactors: Pyridoxal pyrophosphate
CoA; lipoic acid • Products: Alanine; α-ketoglutarate
• Products: Acetyl CoA; CO2; NADH • Purpose: Produce alanine, which then acts to
• Regulation: Inhibited by acetyl CoA, NADH, carry amino groups from muscle to the liver
and ATP • Reaction: Reversible
• Purpose: Produce acetyl CoA for entry into citric
acid cycle and fatty acid synthesis LACTATE DEHYDROGENASE
• Reaction: Irreversible
• Location: Cytosol
PYRUVATE CARBOXYLASE • Products: Lactate; NAD+
• Regulation: Stimulated by high NADH-NAD+
• Location: Mitochondria ratio
• Cofactors: Biotin • Purpose: Replenish NAD+ stores
• Products: Oxaloacetate • Reaction: Reversible in liver, heart, and muscle
• Regulation: Stimulated by acetyl CoA
• Purpose: Produce oxaloacetate for use in citric
acid cycle and gluconeogenesis
• Reaction: Irreversible
9

CH02.indd 9 11-08-2017 15:03:15

 PENTOSE-PHOSPHATE PATHWAY

Glucose-6-Phosphate
+
Glucose-6-Phosphate NADP
Dehydrogenase
NADPH
2
6-Phosphogluconolactone
H2O
Gluconolactonase
+
H

6-Phosphogluconate
6-Phosphogluconate NADP+
Dehydrogenase
NADPH + CO2 Oxidative
Nucleotide Ribulose-5-Phosphate Portion
Synthesis
Non-oxidative
Ribose-5-Phosphate Xylulose-5-Phosphate Portion
Transketolase

Sedoheptulose-7-Phosphate Glyceraldehyde-3-Phosphate
Transaldolase
Glycolysis
Erythrose-4-Phosphate Fructose-6-Phosphate
Transketolase
Xylulose-5-Phosphate Glyceraldehyde-3-Phosphate

10

CH02.indd 10 11-08-2017 15:03:16

 PENTOSE-PHOSPHATE PATHWAY

• Location: Cytoplasm of cells of the liver, adrenal cortex, and lactating mammary glands.
• Substrate: Glucose-6-phosphate.
• Oxidative portion: Irreversible. Rate-limiting step.
▶ Generates two NADPH, which can then be used in fatty acid synthesis and cholesterol synthesis and
for maintaining reduced glutathione inside RBCs.
• Nonoxidative portion: Reversible.
▶ Generates intermediate molecules (ribose-5-phosphate; glyceraldehyde-3-phosphate; fructose-6-­
phosphate) for nucleotide synthesis and glycolysis.
• Regulation: Key enzyme in the pentose-phosphate pathway is glucose-6-phosphate dehydrogenase.
Levels of glucose-6-phosphate dehydrogenase are increased in the liver and adipose tissue when large
amounts of carbohydrates are consumed. Glucose-6-phosphate dehydrogenase is stimulated by NADP+
and inhibited by NADPH and palmitoyl-CoA (part of the fatty acid synthesis pathway).
• Purpose: Functions as an alternative route for glucose oxidation that does not directly consume or produce
ATP. Also acts to replenish NADPH+ stores.

10

CH02.indd 10 11-08-2017 15:03:16

 METABOLISM OF FRUCTOSE

osphate Dihydroxyacetone
1-Ph
tose- se Phosphate 2
Fruc Aldola
Fructokinase se Glyceraldehyde-3
Fructose Fructose-1-Phosphate Trio se
Fruc n a Phosphate
tose- K i
1-P Glyceraldehyde
ATP
ADP Aldo hosphate
lase
NADH ATP ADP

NAD + Glycolysis

Glycerol

• Location: Fructose metabolism takes place primarily in the cytoplasm of cells of the liver.
• Substrate: Fructose (which is derived from breakdown of sucrose in small intestine).
• Purpose: Allows fructose to be converted into intermediate molecules in the glycolysis pathway. Since
this pathway bypasses the rate-limiting step in glycolysis, fructose is metabolized to pyruvate more
rapidly than glucose.
• Results: Generates two intermediate molecules of glycolysis for each molecule of fructose. Requires
two ATP.

11

CH02.indd 11 11-08-2017 15:03:16

 POLYOL PATHWAY

Sorbitol
Aldose Reductase Dehydrogenase
Glucose Sorbitol Fructose

NADPH NAD+
NADP+ NADH
H+ H+

• Location: Conversion of glucose to fructose occurs primarily in the cytoplasm of cells of the liver, ovaries,
and seminal vesicle. Schwann cells as well as cells of the retina and kidneys can only convert glucose to
sorbitol because they only have aldose reductase.
• Substrate: Glucose; NADPH; NAD+.
• Purpose: Used to handle excess glucose not used for energy (due to saturation of hexokinase) by forming
fructose or sorbitol from glucose.
• Results: In cells with both aldose reductase and sorbitol dehydrogenase, one molecule of fructose is
generated
­ for each molecule of glucose, which can then be re-entered into the glycolysis pathway. In cells
with only aldose reductase, one molecule of sorbitol is generated for each molecule of glucose. These
reactions do not require ATP.
• Clinical implications: In cells without sorbitol dehydrogenase (e.g., nervous system, kidney, eyes),
sorbitol
­ can accumulate in the setting of hyperglycemia. This can lead to osmotic damage of these cells
with resulting organ dysfunction.

11

CH02.indd 11 11-08-2017 15:03:17

 METABOLISM OF GALACTOSE

Galactose-1-Phosphate
Galactokinase Uridyl Transferase
Galactose Galactose-1- Glucose-1- Glucose-6- Glycolysis or
Phosphate Phosphate Phosphate Gluconeogenesis 2
ATP ADP UDP-Glucose UDP-Galactose
Aldose
Reductase
UDP-Glucose-4 Epimerase

Galactitol

• Location: Galactose metabolism takes place primarily in the cytoplasm of cells of the liver.
• Substrate: Galactose (which is derived from breakdown of lactose in small intestine).
• Purpose: Allows galactose to be converted into intermediate molecules in the glycolysis or gluconeo-
genesis pathway.
• Results: Generates one intermediate molecule of glycolysis or gluconeogenesis for each molecule of
galactose. Requires one ATP.
• Notes: Galactose can also be metabolized in an alternative pathway to form galactitol via aldose
reductase. High levels of galactitol (present in galactokinase deficiency) can result in osmotic damage
to sensitive tissues, such as the lens of the eye.

12

CH02.indd 12 11-08-2017 15:03:18

 METABOLISM OF LACTOSE

Glucose
se
Lacta
Lactose
Lacta
se
Galactose

Galactose
Metabolism

Glucose-6-Phosphate

• Location: Lactose metabolism takes place primarily in the cytoplasm of cells of the intestine.
• Substrate: Lactose.
• Purpose: Allows lactose to be converted into glucose or intermediate molecules (e.g., glucose-6-phos-
phate) in the glycolysis or gluconeogenesis pathway.
• Results: Generates one molecule of glucose or glucose-6-phosphate for each molecule of lactose. Does
not require ATP.
• Clinical implications: Lactase (also known as β–galactosidase) deficiency can lead to diarrhea, due to
high levels of lactose in the intestinal lumen resulting in osmotic transport of water into the colon.

12

CH02.indd 12 11-08-2017 15:03:19

 GLUCONEOGENESIS

P • Location: Liver, kidney, and intestine; does not occur in skeletal

Pyruvate Car yruv muscle because muscle lacks glucose-6-phosphatase. The first reac-
bo ate
xy
las
e
tion (catalyzed by pyruvate carboxylase) takes place in the mitochon- 2
dria, whereas the rest of the reactions occur in the cytosol.
• Requirements to make one glucose:
Oxaloacetate ▶ Two pyruvate
P Four ATP and two GTP
PE ylase ▶
ox ▶ Two NADH
C arb
▶ Six H2O
Phosphoenolpyruvate

Gluconeogenesis
• Key enzymes (all are irreversible):
Glycolysis

▶ Pyruvate carboxylase (requires biotin)

Glycolytic ▶ Activators: acetyl CoA
Enzymes
▶ Inhibitors: ADP
▶ PEP carboxylase
Fructose-1,6-Bisphosphate ▶ Inhibitors: ADP
▶ Fructose-1,6-bisphosphatase (rate-limiting step)
Fructose-1,6-Bisphosphatase ▶ Activators: cAMP; glucagon
▶ Inhibitors: AMP; insulin; fructose-2,6-bisphosphate
Fructose-6-Phosphate ▶ Glucose-6-phosphatase
• Diseases: Deficiency in any of the gluconeogenic enzymes leads to
Glycolytic
Enzymes hypoglycemia.
• Notes: Odd-chain fatty acids can also undergo gluconeogen-
Glucose-6-Phosphate
esis because they yield a propionyl-CoA, which is transformed into
Glucose-6-Phosphatase succinyl-CoA via propionyl-CoA carboxylase. Succinyl-CoA then
enters the citric acid cycle to form oxaloacetate, which can be used
Glucose
for gluconeogenesis.
13

CH02.indd 13 11-08-2017 15:03:20

 CORI CYCLE

MUSCLE Glucose Lactate • Description: This biochemical cycle describes

the transport of substrates, generated by gluco-
neogenesis, between the liver and the skeletal
muscle.
• Function: Lactate created by active muscle is
Glucose
taken up by the liver and converted to glucose
SERUM Lactate
through gluconeogenesis. The liver releases
resynthesized glucose back into the bloodstream
for use by the active muscles.
• Purpose: This transfer of excess reducing
equivalents from the muscle to the liver allows
LIVER Glucose Lactate the muscle to function anaerobically, netting
two ATP molecules per glycolytic cycle.

13

CH02.indd 13 11-08-2017 15:03:20

Another random document with
no related content on Scribd:
see such a living proof. She is my little Jane as she was when a child
—my little Jane—my darling! Mrs. Lanier, will you excuse me!—the
sight of her has quite unnerved me”; and suddenly sinking into a
chair he pressed the child to his heart and hid his face on her bright
golden head.
What passed between Lady Jane and her grandfather, Mr. and
Mrs. Lanier never knew, for they slipped quietly out of the room, and
left the cold, stern man alone with the last of his family—the child of
that idolized but disobedient daughter, who had caused him untold
sorrow, and whom he had never forgiven until that moment, when he
held in his arms, close to his heart, the child, her living image.
It was some time before Mr. Chetwynd appeared, and when he did
he was as cold and self-possessed as if he had never felt a throb of
emotion, or shed a tear of sorrow on the pretty head of the child, who
held his hand, and prattled as freely and confidingly as though she
had known him always.
“What will Mother Margaret say,” she exclaimed, looking at Mrs.
Lanier with wide, glistening eyes, “when I tell her that I’ve found Tony
and my grandpapa both in one Christmas? I never saw a grandpapa
before. Pepsie read to me about one in a book, and he was very
cross; but this one isn’t. I think he’s very good, because he says that
he will give me everything I wish, and I know I shall love him a great
deal.”
“Now, Lady Jane, confess to me, and I’ll never tell,” whispered
Arthur with an air of great secrecy. “Which do you love best, Tony or
your new grandpapa?”
She raised her clear eyes to the roguish face of the boy with a little
perplexed smile, and then replied unhesitatingly: “Well, I’ve known
Tony longer, but I think I’ll love my grandpapa as well by and by,
because, you know, he’s my grandpapa.”
Arthur laughed heartily at the clever way in which she evaded the
question, and remarked to Mrs. Lanier that Lady Jane would wind
her grandfather around her little finger before a month was over.
Which prediction was likely to prove true, for Mr. Chetwynd did not
seem to have any other interest in life than to gratify every wish the
child expressed.
“She has taken complete possession of me,” he said to Mrs.
Lanier, “and now my greatest happiness will be to make her happy.
She is all I have, and I shall try to find in her the comfort her mother
deprived me of.”
In spite of his affection for the child, his feelings did not soften
toward the mother; he could not forget that she had disappointed him
and preferred a stranger to him; that she had given up wealth and
position to bury herself in obscurity with a man he hated. It was a
bitter thought, yet he would spare no pains to solve the mystery that
hung over her last days.
Money and influence together soon put the machinery of the law in
motion; therefore it was not a month after Mr. Chetwynd’s arrival in
New Orleans before everything was as clear as day. The young
widow was traced to Madame Jozain’s; there were many who
remembered her death and funeral. The physician’s certificate at the
Board of Health bore the name of Dr. Debrot, who was found, and
interviewed during one of his lucid moments; he described the young
mother and child, and even remembered the blue heron; and his
testimony, sad though it was, was still a comfort to Jane Chetwynd’s
friends. She had died of the same fever that killed her husband, and
she had been carefully nursed and decently buried. Afterward, the
Bergeron tomb was opened, the remains identified, and then sent to
New York to rest with her mother, in the stately Chetwynd tomb, in
Greenwood cemetery.
Then a careful search was made for her personal effects, but
nothing was recovered except the watch that Paichoux was fortunate
enough to secure. Mr. Chetwynd handed Paichoux a large check in
exchange for it, but the honest man refused to take any more than
he had paid Raste Jozain in order to get possession of it. However,
the millionaire proved that he was not ungrateful nor lacking in
appreciation, when he presented him with a rich, plain watch suitably
inscribed, from the donor to a most worthy friend. And when the
pretty Marie was married, she received from the same jeweler who
made the watch an exquisite silver tea-service, which was the pride
of her life, and which was cherished not only for its value, but
because it was a gift from Lady Jane’s grandpapa.
Mr. Chetwynd made a number of visits to Good Children Street in
company with Mrs. Lanier and Lady Jane, and there were a great
many long conversations between Mam’selle Diane, the millionaire,
and the banker’s wife, while Lady Jane played with her jolly little
friend, the canary, among the branches of the rose-bush. During
these conversations there was a great deal of argument and anxious
urging on the part of the visitors, and a great many excuses and
much self-depreciation on the part of the gentle, faded lady.
“I have been buried so long,” she would say pathetically, “that the
great world will appal and confuse me. I shall be like a blind person
suddenly made sensible of the light.”
“But you will soon become accustomed to the light,” urged Mrs.
Lanier.
“And I might long for seclusion again; at my age one cannot easily
change one’s habits.”
“You shall have all the seclusion you wish for,” said Mr. Chetwynd
kindly.
“Besides I am so old-fashioned,” murmured Mam’selle Diane,
blushing deeply.
“A quality which I greatly admire,” returned Mr. Chetwynd, with a
courtly bow.
“And think how Lady Jane loves you,” said Mrs. Lanier, as if to
clinch the argument.
“Yes; my love for her and hers for me are the strongest points in
the situation,” replied Mam’selle Diane reflectively; “when I think of
that I can hardly refuse to comply with your wishes.”
At that time it seem as if Lady Jane acted the part of fairy
godmother to those who had been her friends in her days of
adversity; for each one had only to express a wish and it was
gratified.
 Pepsie’s cottage in the country was about to become a reality. In
one of the charming shady lanes of Carrollton they found just such a
bowery little spot as the girl wished for, with a fine strip of land for a
garden. One day Mr. Chetwynd and Lady Jane went down to Good
Children Street and gave the deed of it to Mademoiselle Madelon
Modeste Ferri, which was Pepsie’s baptismal name, although she
had never been called by it in all her life. The little cripple was so
astonished and delighted that she could find no words of thanks; but
after a few moments of very expressive silence she exclaimed: “After
all, my cards were right, for they told me over and over that I should
go to live in the country; and now I’m going, thanks to Lady Jane.”
When little Gex was asked what he most wished for in the world,
he hesitated for a long time, and finally confessed that the desire of
his life was to go back to Paris.
“Well, you shall go, Mr. Gex,” said Lady Jane confidently, “and I
shall see you there, because I’m going to Paris with grandpapa very
soon.”
It is needless to say that Gex went, and the little shop in Good
Children Street saw him no more forever.
And Margaret—the good Margaret. What could Lady Jane do for
her? Only the noble woman and the destitute orphans could testify to
the generous aid that came yearly in the shape of a check for a large
amount from Lady Jane for dear Mother Margaret’s home.
“And Mam’selle Diane,—dear Mam’selle! what can I give her?”
asked Lady Jane eagerly.
“We have our plans for Mam’selle Diane, my dear,” said Mrs.
Lanier. “There is only one thing to do for her, and that is to take her
with you. Your grandpapa has begged her to take charge of your
education. Poor, lonely woman; she loves you dearly, and in spite of
her reluctance to leave her seclusion, I think she would go to the
world’s end with you.”
And so it was arranged that when Mr. Chetwynd and Lady Jane
left New Orleans, Mam’selle Diane d’Hautreve went with them, and
the little house and tiny garden were left to solitude, while the jolly
canary was sent to keep Tony company in Mrs. Lanier’s
conservatory.
 CHAPTER XXXIII
AS IT IS NOW

A LL this happened years ago, some ten or twelve, more or less,

and there have been many changes in that time.
In front of the iron railing where Lady Jane clung on that cold
Christmas eve, peering into the warmth and light of the Orphans’
Home, there is now a beautiful little park, with magnolias, oaks,
fragrant white jasmine, and pink flowering crape-myrtle. The grass is
green, and the trees make shadows on the pretty little pond, the tiled
bridge and shelled walks, the cactus and palmetto. Flowers bloom
there luxuriantly, the birds sing merrily, and it is a spot beloved of
children. Always their joyous laugh can be heard mingled with the
songs of birds and the distant hum of many little voices in the
Orphans’ Home a few paces away.
In the center of that square on a green mound, bordered with
flowers, stands a marble pedestal, and on that pedestal is a statue. It
is the figure of a woman, seated and holding a little orphan to her
heart. The woman has a plain, homely face, the thin hair is combed
back austerely from the broad forehead, the eyes are deep-set, the
features coarse, the mouth wide. She is no high-born dame of
delicate mold, but a woman of the people—untaught, honest, simple,
industrious. Her plain gown falls around her in scanty lines; over her
shoulders is modestly folded a little shawl; her hands, that caress the
orphan at her side, are large and rough with honest toil; but her face,
and her whole plain figure, is beautiful with purity and goodness. It is
Margaret, the orphans’ friend, who, though a destitute orphan
herself, by her own virtue and industry earned the wealth to found
homes and asylums, to feed and clothe the indigent, to save the
wretched and forsaken, and to merit the title of Mother to the
Motherless.
 And there sits her marble image, through summer’s heat and
winter’s cold, serene and gentle, under the shadow of the home she
founded, and in sound of the little voices that she loved so well; and
there she will sit when those voices are silent and those active little
forms are dust, as a monument of honest, simple virtue and charity,
as well as an enduring testimony to the nobility of the women who
erected this statue in respectful recognition of true greatness under
the homely guise of honest toil.
If one of my young readers should happen near this spot just at
the right moment on some fine evening in early spring, he or she
might chance to notice an elegant carriage drawn by two fine horses,
and driven by a sleek darky in plain livery, make the circuit of the
place and then draw up near the statue of Margaret, while its
occupants, an elderly woman of gentle and distinguished
appearance, and a beautiful young girl, study the homely, serene
face of the orphans’ friend.
Presently the girl says reverently, “Dear Mother Margaret! She was
a saint, if earth ever knew one.”
“Yes; she was a noble woman, and she came from the poor and
lowly. My dear, she is an example of a great truth, which may be
worthy of consideration. It is, that virtue and purity do not disdain to
dwell in the meanest shrine, and that all the titles and wealth of earth
could not ennoble her as her own saintly character has done.”
The occupants of the carriage are Lady Jane and Mam’selle Diane
d’Hautreve.
The beautiful child is now a beautiful girl of seventeen. Her
education is finished, and she has not disappointed the expectations
of her friends. At home and abroad she is not only known as the
Chetwynd heiress, but also for her many accomplishments, as well
as for her beauty and charitableness. And her wonderful voice, which
time has enriched and strengthened, is a constant delight to those
who hear it, although it is never heard in public, save in the service
of God, or for some work of charity. The poor and the lowly, the sick
and the dying have often been carried to the very gates of heaven on
its melodious strains, and the good sisters and grateful little orphans
in Margaret’s Home count it a day long to be remembered when
Lady Jane sits down among them and sings some of the hymns that
she loved so well in those old days when she herself was a
homeless little orphan.
Mr. Chetwynd still likes to spend part of the year in Paris; but he
has purchased a beautiful winter home in one of the lovely streets in
the garden district, not far from Mrs. Lanier, and Lady Jane and
Mam’selle Diane spend several months every spring in its delightful
seclusion.
And here Madelon comes to bring her delicious cakes, which she
now sells to private customers instead of having a stand on the Rue
Bourbon; and Tante Modeste often rattles up in her milk cart, a little
older, a little stouter, but with the same bright face; and on the same
seat where Lady Jane used to sit is one of Marie’s little ones, instead
of one of her own. “Only think, my dear,” she says proudly, “Tiburce
has graduated, and now he is studying law with Marie’s husband,
who is rising fast in his profession.”
But among all her happy hours there are none pleasanter than
those she spends with Pepsie in the pretty cottage at Carrollton,
when the bright-faced little cripple, who seems hardly a day older,
spreads out her beautiful needlework and expatiates eloquently on
the fine results she obtains from the Paris patterns and exquisite
material with which she is constantly supplied. She is a natural little
artist with the needle, her dainty work sells readily and profitably, and
she is in a fair way to become rich. “Just think,” she says with one of
her broad smiles, “I could buy a piano now myself, if I wanted to, and
perhaps I shall, so that you can play to me when you come.”
During sunny mornings, on a certain lawn in the garden district,
there is nearly always a merry party playing tennis, while a gentle-
faced woman sits near holding a book, which she seldom reads, so
interested is she in watching a golden-haired girl and a handsome
young man, who frequently interrupt the game to point out the grave
antics of a stately blue heron, that stalks majestically about the lawn
or poses picturesquely on one leg under a glossy palm.
 But we must not approach the border-land of romance. Lady Jane
is no longer a child, and Arthur Maynard is years older than the boy
who gave her the blue heron.

THE END
 Transcriber’s Notes

pg 14 Changed: if you thing it’s right

to: if you think it’s right
pg 133 Changed: LADY JANE FINDS A MUSIC-TEACHFR
to: LADY JANE FINDS A MUSIC-TEACHER
pg 152 Changed: You didn’t wear a handkerchef over your ears
to: You didn’t wear a handkerchief over your ears
pg 168 Changed: annoyed at Pespie’s air of secrecy
to: annoyed at Pepsie’s air of secrecy
*** END OF THE PROJECT GUTENBERG EBOOK LADY JANE ***

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