Intro to Metabolism

With Ryan and Maggie

Metabolism

● The sum of an organism's chemical reactions

● Starts with a specific molecule (glucose) and ends with a specific product

(lactate/ Acetyl CoA)

● Catabolic = Release of energy by breaking down large molecules into smaller

ones (simple compounds)

○ Break down glucose in order to get energy (ATP)

● Anabolic = Consumes energy to build complex molecules

○ Glucose + glucose + glucose etc will yield glycogen

■ Requires energy

● Amphibolic = Connection between the catobolic and anabolic pathways of

metabolism

Energy yield. Oxygen consumption, and CO2 production

● Dont need to know this table

● Take away ? Protein and carbs yield nearly the same amount of energy

● Fats yield much high energy

○ Nearly twice as much per equivalent weight

Kwashioshor vs Marasmus (nutrient deficient)

● Kwashiorkor - slightly older children

○ A disease characterized by a decreased intake of protein
Malurutrity

○ Still efficient intake of carbs and fats though and you still meet your daily average

dena requirement of calories

renin Plasma op

○ Due to low protein intake, edema will be present (hypoproteinemia) due to oncotic pressure

iver

○ Body starts breaking down muscle in order to get the proteins/amino acids needed

○ Fatty liver

● Anemia can present

● Marasmus - complete lack of nutrition - infants and very young

○ Don't get carbs, proteins, or fat

○ Muscle wasting as well

○ Loss of fat/tissue, variable edema

Kwashioshor vs. Marasmus

Acetyl CoA and breakdown of fat, protein, and carb

● Acetyl CoA is produced from 3 pathways

● Will then enter citric acid cycle

● ATP production via ETC in mitochondria

● 3 “hubs”

○ Glucose 6 phosphate

○ Pyruvate

○ Acetyl CoA

GH 660in Ever
Carbohydates

GGP

● Carbohydrates → glucose →glucose 6 phosphate 610

○ Glucose 6 phosphate can also come from liver (glycogen) by glucose 1 phopshate

● Amino acids and pyruvate can also produce glucose 6 phosphate by a process

called gluconeogenesis

● Glucose 6 phosphate is a molecule that can have different destinies

○ Can be converted back into glycogen for storage

○ Precursor for pentose phosphate pathway which is used to create nucleotides

Autosomal recessive
f

Von Gierke Disease Gbp Defriort

liver bGcucosefainsulinfG1ycogen
Enlarged

● Can cause seizures due to low glucose levels

● Hepatomegaly due to increased glycogen storage

●
ylow6lvosreas.u0jf.n
Hypertriglycemia due to low levels of insulin in blood

● Lactic acidosis competes with uric acid in renal tubule →uricacid builds up in

blood manifesting as gout

Lactate pyruvate
Pyruvate

Alanine Pyruvate

From
0g 6hm

●
t
Can also come lactate via muscle cell fermentation

○ Cori cycle

■ Lactate from muscle will go to the liver and be converted to pyruvate

■ This pyruvate will then convert into glucose by gluconeogenesis

Can also come the deamination of alanine

●
○ Structure is very similar 0

Tea
■ So this means pyruvate can be transaminated into alanine

● Link between protein/carb metabolism

● Pyruvate to acetyl CoA by taking off the carboxyl

Voigidative

decarboxylation

coz

ketones actoxicot
Acteyl CoA

● Two main sources of acetyl CoA are pyruvate and fatty acids (breakdown of

fat)

● Not the main source, but amino acids/ketone bodies can also produce acetyl

CoA

○ Usually seen in severe starvation

● Ketone bodies are useful in the brain as they are converted to acetyl CoA in

the brain when glucose levels are low

○ Feed into the citric acid cycle for energy

● Important to note: acetyl CoA can not convert back into pyruvate**

IT

● Also used to build fatty acids, two acetyl CoA’s at a time

○ Also precursor for cholesterol/steroid hormone synthesis

Acetycot Pyro

t
H2O

Acety CoA coz

Acetyl CoA fates

Steniods cholesterol

1. Get fully oxidized to Co2 and H20 (TCA cycle)

ketones

2. Serve as precursor for steroids and cholesterol

3. Transform into ketone bodies

a. Acetoacetate and 3-hydoxybutyrate

b. Decarboxylation of acetoacetate will yield acetone

decarbox

Summary

 Inhib

ATP citrate NADH

Activator vs. Inhibitor

Activate ADP

ATP i

ATpecifrate

Dp preserse means

Ap

is being

used

Glucose and carbohydate metabolism

● Glucose gets broken down into pyruvate →acetyl coa → citric acid cycle

→electron transport chain

Glycogen phosphate can enter glycolysis pathway or the opposite route, and

●
produce glycogen (glycogenesis) Glycogen
I

● OR Pentose phosphate to produce ribose which is important for nucleotide

production

Lipids

● Centered around cholesterol and fatty acids

● Major source is from diet or de novo synthesis of acetyl coA from amino

acids or carbs

● Fatty acids can be oxidized into acetyl coA (beta-oxidation)

● Fatty acids can also be esterified to glycerol to produce triacylglycerol (fat

storage)

Deamination UREA
Amino acids

●Some are essential

●Others can be formed from other intermediates in metabolic pathways by

same transamination reactions Thets

○ Alanine from pyruvate whey its not an essay ay

a ● Deamination of a molecule will yield a free amino nitrogen n

○ Gets excreted in urine as UREA

Sosa gets excreted
by liver

● Precursor for:

○ Neurotransmitters (tyrosine to dopamine/NE/Epi)

○ Hormones (tyrosine to melanin)

○ Purine and pyrimidine synthesis

● After deamination of an amino acid that carbon skeleton can be used to

produce energy via TCA cifnLAC.de

○
J efiLyoEedizeq
Or used in gluconeogenesis or form ketone bodies from acetyl CoA

Glucose from non carb carbon

Importance of transamination/deamination reactions

Toffs

non protein N Destinies

AAdkeyto

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Aka area


Glycogen or GPS 66P enters Glycolysis

Stress and Metabolism

● Adrenaline is associated with metabolic changes

● Liver

○ Has the same effects of glucagon

● Muscle

○ Main target of adrenaline GLP

○ Will stimulate the breakdown of glycogen into glucose 1 phosphate which will then convert

●
into glucose 6 phosphate (enter glycolysis)
Adrenaline will increase tissue oxygenation
GGT

● Will prime muscle to produce nutrients

○ Glucose for energy

Adrenaline and Glucagon

● Both increase levels of glucose 1 phosphate B Ggp

Phosphorylase

● Both activate glycogen phosphorylase 9 Glycogen

○ Enzyme used to break down glycogen

Both activate protein kinase A

●
●
Q CacAS
Protein kinase A (when activated by glucagon/adrenaline) will lead to the

phosphorylation of glycogen phosphorylation B (inactive) converting it into

glycogen phosphorylase A (active) now p

ed

● Adrenaline receptors are found in muscle

○ Produce glucose 1 phosphate from glycogen breakdown and then again, convert into glucose

6 phosphate

go.sn GP GGP

Admire 9 CRA
Stress

● Activates hypothalamic-pituitary adrenal axis

○ Releases corticotropin releasing hormone CRA CRHAB

○ Anorexigenic effects

■ Might explain why we dont eat when we’re all studying

○ Stimulate catecholamine release

■ Hypophagia

■ Weight loss

■ Effects on white/brown adipose tissue
nsulin

be ○ Insulin release is inhibited

■ You want more glucose in your blood

● Chronic stress and SNS with weight GAIN

○ Neuropeptide Y and glucocorticoid release

from non carb carbon

production
Stress

Glucose

● Reliance on gluconeogenesis

●

hypermetabolism

● Acute phase protein synthesis

● Nutrient requirement is increased

Glucose
ycoge

● Increased glucagon production - need more glucose in blood

● Increased cortisol (stress hormone) levels - induce gluconeogenesis - need

more glucose

● Increased production of epinephrine/NE - stimulate glycogen breakdown -

more glucose

● Insulin resistance is a possibility in the increased release of glucose into

blood


IP 81C M

Stress continued

● Stress can also be from damage in the body (if you got a cut on your knee)

● Release of inflammatory mediators like C-reactive protein and TNF-alpha

● Negative nitrogen balance - increased breakdown of protein and decreased

protein synthesis

○ Rely on proteins for a source of glucose

Catabolis not skeletal muscle

B sensitive to Glucose levy

Pancreas and its hormones

produces

● Beta cells - insulin - when sugar levels are high

● Alpha - glucagon
one

● Delta cells - somatostatin

● Gamma cells - pancreatic polypeptide

● Epsilon cells - secretes ghrelin

hunger

9 Glucose levels in Blood

Glucagon

● Works with insulin to keep a balance of blood glucose levels (euglycemia)

● Increases blood glucose Glucose Tose P

● Secreted from alpha cells

eouG6p

● Secreted during fasting y

only Glycogen can

● Inhibits glycogen synthase from

○ Activates glycogen phosphorylase (breaks down glycogen) leare liver

○ Activates lipid metabolism breakdown

○ Activates AA breakdown

● Glucagon’s affect on liver

○ Will breakdown glycogen and form glucose 6 phosphate (not glucose 1 phosphate like in

muscle**)

○ Glucose 6 phosphate is charged so it can't leave the liver onlyyo P itcarenter

■ Will lose the phosphate group (by glucose 6 phosphaTASE) and enter blood to reach

RBC’S and brain



Regulators of glucagon release

Pstin

i hits

Insulin and glucagon balance

● Insulin release inhibits glucagon release

○ Mechanism of this glucose - induced inhibition release of glucagon is still not fully

understood

● Gluconeogenic amino acids to glucose

○ Glucagon stimulates this

● Release of free fatty acids and VLDL (transports triglycerides)

○ Glucagon stimulates this

Important take away with insulin vs. glucagon

GUI

Transport and fate of lipids in the gut

O

● Triacylglycerol from diet get broken down into monoacylglycerols and fatty

acids to absorb ed

fur

● Once absorbed, fatty acids get re-esterified in intestinal mucosa to they can

be packaged into a chylomicron along with fat soluble vitamins (A,D,E,K)

●
O
Triacylglycerols are not directly taken up by liver

○ Metabolized instead by tissues with lipoprotein lipase enyzmes ytyphatesystem

○ Leaves what’s called a chylomicron remnant

■ Degraded by liver

● Can also have lipogenesis for another source of long chain fatty acids

Chylomicron and transport of fatty acids

vet

Metabolism in the liver

Chor

● Nutrients absorbed via hepatic vein

● Regulates blood concentration of water soluble metabolites

○ Glucose

● Fed state: liver produces glycogen or fatty acids

● fasting state: liver (with kidney) will convert non-carb metabolites into carbs

(glucose) for energy

● Blood glucose levels are important for brain and RBC’s

○ Glucose is the preferred fuel for brain

RBC’s can only use glucose since they don't have a mitochondria

●
○
o
Synthesizes albumin (major carrier protein) and urea

liner synthesizes Album.h Greer

Metabolism in adipose tissue

● Triacylglycerol main reserve form for fats

● Lipolysis - fatty acids and glycerol into blood

● Glycerol can be used for gluconeogenesis since it has a carbon backbone

● Fatty acids (not water soluble) must bind with albumin to travel through

blood

● Fatty acids are taken up by all tissues besides brain and RBC’s

● VLDL - transports triacylglycerol from liver to tissues

● Liver can oxidize fatty acids into ketones which can be used as fuel in

prolonged fasting

○ Ketogenic diet

Metabolism in the brain

● Protected by the blood brain barrier

● Not supposed to have infections/inflammation there so naturally we dont

have a huge repertoire to fight off infections

○ Very damaging if pathogen/toxin enters

● So how are nutrients going to cross this barrier?

Magela/Maggie

Simple diffusion transport

● Regular capillaries have a thin layer

● Small molecules cross from the blood to the tissues via passive diffusion

down concentration gradient

● Transcytosis- larger molecules get endocytosed and then released on the

other side by exocytosis

● Small windows- fenestra

● Facilitated passive transport

○ Brain capillaries- several layers, NO fenestra

■ Capillaries without a fenestra joined by TIGHT junctions, encompassed by a basal

membrane, surrounded by astrocytes and pericyte

■ How do things get through?

● Transporter proteins allow on either side of the brain capillary

● Carbon dioxide, oxygen and water can freely diffuse, do not require a transporter

Brain
Glucose transportation across the brain

● GLUT1 transporters- facilitated diffusion

●
○
00
GLUT1 transporters also found in cardiac muscle and RBCs
MCT1 transporters- lactate, pyruvate and ketone bodies (monocarboxylic

acids)

● Non-essential AAs are blocked from transport by BBB

● ONLY essential AAs have transporters

○ PVT TIM H(A)LL

MUT ketones

Primary active transport

● Requires ENERGY! ATP

● Moves molecules against their concentration gradient

● Uniport- only one molecule is transfered

● Symport- two molecules transferred in the SAME direction

● Antiport- two molecules transferred BUT in OPPOSITE directions

Secondary active transport

● Dependent on primary active transport

● The channel itself does not hydrolyze ATP but uses the energy from the

gradient created by primary transport channels (e.g. the Na+/K+ ATPase

pump)

● Example:

○ Na+/glucose transporter

■ Na+/K+ ATPase moves sodium out of the cell, creating a concentration gradient with

low sodium inside the cell

■ Na+/glucose transporter co-transports Na+ and glucose INTO the cell

● Glucose now is able to be transported against its concentration gradient by

co-transporting Na+ from area of high concentration (outside the cell) to low

concentration (inside the cell)

Brain metabolism

What happens when there’s hypoglycemia? AM CTI

● Initially, GLUT1 transporter compensates

● Then upregulation of MCT1

○ Increased transport of ketone bodies and pyruvate to feed TCA

● Decreased glucose → decreased energy

○ Brain requires a lot of ATP to maintain membrane gradient and neurotransmitter synthesis

○ COGNITIVE DYSFUNCTION

■ Can lead to severe brain damage

Brain metabolism

What happens when there’s hypoxia in the brain?

● Hypoxia- lack of O2
o

○ Electron transport chain has NO FINAL electron acceptor

○ Brain shuttles through anaerobic fermentation

■ Lactic acid buildup

■ Acidosis (decreased pH)

■ Irreversible brain damage!

aerobially aneendially
Muscle

● LITTLE free glucose in the muscle

pfbooger

○ Gets phosphorylated following uptake

○ Trapped as glycogen

○ When glycogen is broken down into glucose in the muscle, ONLY the muscle can use that

glucose

■ That glucose cannot be transported to other areas of the body

● Muscle can use glucose both aerobically and anaerobically

● Can synthesize muscle protein from plasma amino acids and can ALSO

supply amino acids in the setting of starvation for gluconeogenesis

Energy consumption of muscle

● At rest

○ Fatty acids → citric acid cycle → oxidative phosphorylation (requires O2) → ATP synthesis

○ Plenty of oxygen and most of ATP production by aerobic respiration

● Moderate activity

○ Fatty and acids in lines Cloidy

focus

○ Glucose
river
■ From the liver! Either from gluconeogenesis or hepatic glycogen
q
○ Plenty of oxygen and most of ATP production by aerobic respiration

D
● Burst of activity IIInary 9

○
rugs
Quick consumption of ATP, large and immediate demand of ATP, not enough O2

■ Demand for increased blood flow (increased O2 delivery)

Dents

■ Phosphocreatine rapidly regenerates ATP by phosphorylating ADP

● Present in LOW concentrations, only sustain muscle for short period of time

○ Will use its own glycogen storage

○ Anaerobic fermentation while it awaits for its oxygen delivery

How can glycogen generate ATP?

● When glycogen is catabolized, it results in the production of

glucose-6-phosphate

○ There is no need to phosphorylate this glucose!

Therefore it requires the use of one less ATP compared to digested glucose in the diet

○
○ Glucose= 2 ATP
o

○ Glycogen→glucose-6-phosphate= 3 ATP

Glycogen

Gbp

Fit
energy source
Cardiac muscle Glucose B High levels or exers Be

● Dependent on aerobic metabolism→ ALWAYS requires O2

● Use FAs as source of energy

● Poor oxygenation → ischemia of cardiac tissue → death of cardiomyocytes

● Very sensitive to pH changes teeth Tony

○ Cannot tolerate acidity produced by anaerobic fermentation

● Can use glucose when there are high glucose levels or when increased

workload (e.g. exercise)

● Can use some lactate

Mike

faacdycogenp.hr pharylas
McArdle Disease

Glycogen Storage disease Type V in muscles

● Cannot breakdown glycogen in muscle cells forty

glucose
Deficiency in muscle glycogen phosphorylase Glycogen

○ Very important enzyme that provides energy during the first few minutes of exercise

○ Patients usually complain of fatigue, muscle pain and cramps

○ Aka exercise intolerance

○ Prolonged exercise → increased blood flow → improved symptoms

■ Class “second wind phenomenon”

whhep
Doing Hurdles
Ardle

Hurdle

msdesdsyntong


Of 1
fpGlycogen Debranching Enzyme
Cori Disease

Branded glycogen

Glycogen Storage disease Type III or Forbes Disease

ocosidaseJ

● Autosomal recessive A 46 co

● Deficiency of glycogen debranching enzyme

○ Alpha-1,6-glucosidase

● Accumulation of branched glycogen chains in lysosomes of cells

○ Aka limit dextrins

● Symptoms

○
○
Hepatomegaly (big liver)
Hypoglycemia
Hepato megaly

keBbranchg

Cori

is 16 climbing tre.es


Compartmentalization

● Mitochondria CTA

○ CTA (carb metabolism)

D lipid

○ Beta-oxidation (lipid metabolism)

○ Ketogenesis

○ Electron transport chain

● Cytosol

○ Glycolysis
ppp

○ Pentose phosphate pathway

○ Fatty acid synthesis

FAS
● Endoplasmic reticulum

○ Triacylglycerol synthesis
E

● Ribosomes

○ Proteins

Compartmentalization continued...

● Separation into organelles

○ E.g. we don’t want to breakdown the FAs we are synthesizing, hence these processes are

separated within the cell

● Separation via impermeable membranes

○ E.g. electrochemical gradient allows for proton gradient NECESSARY for ATP synthesis

● Segregation of enzymes away from substrates

○ E.g. glucokinase in liver sequestered in the nucleus to limit glycolysis until you have high

enough glucose levels that you want to metabolize!

● Metabolic specialization of organs

○ Liver stores glucose via glycogen and delivers glucose to tissue by breaking down glycogen

a e
when needed a

Prolonged starvation

● Depletion of adipose tissue

● Increase protein breakdown

● Death = when proteins are broken down and NOT replaced

● Wasting diseases

○ Cachexia

○ Marasmus

○ Kwashiorkor

De R

Cachexia

Cachexia

● Seen in 50% of cancer patients

○ Accounts for 20% of cancer deaths

○ Can also be seen in COPD, AIDS and viral infection

● Multifactorial syndrome

● Symptoms

○ Weight loss, muscle loss, fat mass loss, anorexia, systemic inflammation, insulin resistance,

hypogonadism, anemia, functional impairment

Girls

at

Cochella look so skinny
like oaths

carar

Lipids

Gmp oils

● Saturated FAs have higher melting points than unsaturated FAs

● Unsaturated fatty acids always in CIS not trans conformation

● Carboxyl head is HYDROPHILIC

● Hydrocarbon tail is HYDROPHOBIC

● Phospholipid bilayer arranges itself spontaneously because of favorable

reaction for polar heads to face hydrophilic environment and nonpolar tails

to face each other

○ Rarely flip!

Lipids continued...

Can be either…

● Structural
○ Amphipathic (both hydrophilic and hydrophobic)
○ Part of thermodynamically favorable membrane formation
○ Cholesterol intercalates at membrane
● Storage
○ Adipose tissue- in the form of triacylglycerols
Lipid signaling
Q
molecules
● Both extracellular and intracellular messengers
● If dysregulated can lead to
○ Inflammation
○ Autoimmune disease
○ Cancer
○ Metabolic, cardiovascular and degenerative disease
● Eicosanoids like prostaglandins and leukotrienes play a role in inflammation
○
I
These eicosanoids are synthesized via COX and 5-lipoxygenase enzymes respectively
■ Aspirin and NSAIDS are COX inhibitors
OO
■ Pain relieving, fever reducing, and anti-inflammatory properties