PROCESS LOCATION SUBSTRATE, END PRODUCTS RATE LIMITING STEP IMPORTANT NOTES

GLYCOLYSIS Cytosol S: GLUCOSE Fructose-6-phosphate → - MAJOR PATHWAY for glucose metabolism

E: 2 molecules of either pyruvate Fructose-1,6,-bisphosphate - Most common: Embden-Meyerhof-Parnas Pathway
(aerobic) or lactate (anaerobic) Step 1
Phosphofructokinase 1 Hexokinase Glucokinase
Most tissues Liver parenchymal cells
Islet cells of pancreas
*Liver activity induced by
INSULIN
(-) Glucose-6-P (-) Fructose-6-p
Low Km, High Affinity High Km, Low Affinity
Low Vmax High Vmax
Phosphorylate glucose and other hexoses

Step 3
PFK-1 PFK-2
Fructose-1,6-bisphosphate Fructose-1,6-bisphosphate
(+) F-2,6-BP, AMP (+) Well fed state, ↑Insulin,
↓glucagon
(-) citrate, ATP (-) fasting state, ↑Glucagon,
↓Insulin

Step 10
- 1 mole phosphoenolpyruvate → 1 ATP
- (+) F-1,6-BP, (-) Glucagon

ATP yield
AEROBIC ANAEROBIC
Consumed -2 -2
Substrate Level 4 4
phosphorylation 1,3-Bisphophoglycerate → 3
phosphoglycerate
(Phosphoglycerate kinase)
PEP → Pyruvate
(Pyruvate kinase)
From NADH 3 or 5 0
Aerobic: NADH → ETC, requires shuttle
GLYCEROPPHOSPHATE (Brain, white
muscles): 3 ATP
MALATE ASPARTATE (Heart, most
tissues): 5 ATP
NET ATP YIELD 5 or 7 2

1|BIOC HEM
 PYRUVATE KINASE: Most common enzyme defect in glycolysis
PYRUVATE DEHYDROGENASE: Most common cause of
congenital lactic acidosis

Fates of Pyruvate
1. Lactate (Anaerobic Glycolysis, LDH)
2. Oxaloacetate (Gluconeogenesis, Pyruvate Carboxylase)
3. Acetyl Coa (TCA, Pyruvate Dehydrogenase)
4. Ethanol (Fermentation, Pyruvate Decarboxylase)
CITRIC ACID CYCLE Mitochondria S: Acetyl CoA Isocitrate → a-ketoglutarate Tricarboxylic Acid cycle, Krebs Cycle
Mitochondrial E: 2 CO2, 1 GTP, 3 NADH, 1 FADH2 - FINAL Pathway for the aerobic oxidation of
matrix (except Isocitrate dehydrogenase carbohydrates, lipids and proteins
SUCCINATE - MAJOR pathway for ATP formation
DEHYDROGENASE
→ inner Cofactors for Pyruvate → Acetyl CoA
mitochondrial 1. Thiamine
membrane) 2. Lipoic Acid
3. Coenzyme A (contains Pantothenic Acid)
4. FAD
5. NAD+

Intermediates – replenished by ANAPLEROTIC reactions

(Pyruvate carboxylase -most impt; glutamine, glutamate, fatty
acids, amino acids, propionyl Coa)
1. Citrate: delivers Acetyl CoA to cytosol for fatty acid
synthesis via citrate shuttle
2. Succinyl Coa: for heme synthesis and activation of
ketone bodies in extrahepatic tissues
3. Malate: may be used for gluconeogenesis

ATP yield for TCA

Acetyl Coa
NADH 3 7.5
FADH2 1 1.5
GTP 1 1
TOTAL 10

Complete Glucose Oxidation

ATP
Glucose → 2 Pyruvate (Glycolysis) 5 or 7
2 pyruvate → 2 acetyl Coa 2 NADH 5
2 Acetyl Coa in Krebs Cycle 10 each 20
TOTAL 30/ 32

2|BIOC HEM
 Amino Acids
Citrate Is Kreb’s Starting Substrate For Making Oxaloacetate Glucogenic Ketogenic Both
C→I (inhibited by FLUROACETATE) Pyruvate Alanine Threonine
I→ K (produces CO2 and NADH) Cysteine Tryptophan
K→ S (produces CO2 and NADH, inhibited by Arsenite and ↑Ammonia) Glycine
S→ S (produces GTP by substrate level phosphorylation) Serine
S → F (produces FADH2) Acetyl CoA Lysine Threonine
M → O (produces NADH) Leucine Tryptophan
PHA
Isoleucine
Tyrosine
a- Glutamate
ketoglutarate Arginine
Histidine
Proline
Glutamine
Succinyl-Coa Methionine Threonine
Valine Isoleucine
Fumarate Aspartate Tyrosine
PHA
Oxaloacetate Aspartate
Asparagine
GLUCONEOGENESIS Liver (90%) S: intermediates of glycolysis and Fructose 1, 6 BP → fructose- - Glucose from NON-CARBOHYDRATE precursors
Kidney (10%) TCA, Lactate (Cori Cycle), 6-P (lactate, AA, glycerol)
Glycerol and propionyl-CoA from - Occurs in condition in which pyruvate dehydrogenase,
Mitochondria and TAG, Carbon skeletons of Fructose 1-6 bisphosphatase pyruvate kinase, PFK1, glucokinase are relatively
Cytosol glucogenic amino acids (Alanine: inactive
Major) Inhibited by F-2,6-BP, AMP - Under fasting conditions, ↑Glucagon
- Regulated by:
Occurring in both CYTOSOL and E: glucose F-2,6-BP is PRO-GLYCOLYSIS 1. Circulating levels of glucagon
MITOCHONDRIA: HUG 2 mol Lactate + 6 ATP → 1 mol 2. Available glucogenic substrates
glucose 3. Allosteric activation of hepatic pyruvate
Heme Synthesis, Urea Cycle, carboxylase by acetyl Coa
Gluconeogenesis 4. Allosteric inhibition of F-1,6-BP by AMP
CORI CYCLE
- Lactate formed by glycolysis in skeletal
Energy requirement of Gluconeogenesis
muscles is transported to liver where it is
- From pyruvate requires 4 ATP + 2 GTP, oxidation of 2
converted back to glucose through
NADH
gluconeogenesis - Energy is derived from fatty acid oxidation

**ALL Carboxylase require BIOTIN

GLYCOGENESIS S: a-D-glucose Elongation of glycogen Chains - GLYCOGENIN: primer for glycogen synthesis when
Liver, muscle
E: glycogen Glycogen synthase glycogen is completely depleted
Cytosol
- Primary glycosidic bond: a(1→4)

3|BIOC HEM
 - Branch points after 8-10 residues: a(1→6)
- UDP is needed to attach glucose to glycogen strand
GLYCOGENOLYSIS S: Glycogen Shortening of Glycogen Chains - Shortening stops when only 4 glucosyl units remains
E: Glucose (liver), G-6-P (muscle) Glycogen phosphorylase

Viagra Pills Cause A Muscle Hardening

POLYOL Glucose → Sorbitol → Fructose Enzymes:
1. Aldose reductase (G→ S): lens, retina, Schwann cells,
liver, kidney, placenta, RBCs, ovaries, seminal vesicles
2. Sorbitol dehydrogenase (S→ F): liver, ovaries, seminal
vesicles
URONIC ACID Liver - Alternative pathway for glucose oxidation
Pathway - No ATP produces
- MAIN Pathway for glucuronic acid and iduronic acid production
- Also synthesizes Ascorbic acid (not possible for guinea pigs and primates because of ABSENCE of L-GULONOLACTONE
OXIDASE)

Glucuronic Acid:
- Essential component of GAGs
- Also required in detoxification reactions of insoluble compounds: Bilirubin, Steroids, Morphine and other drugs
PENTOSE RBCs and tissues S; G-6-P Glucose-6-Phosphate → 6- - Production of NADPH
PHOSPHATE that produce E: NADPH, Ribose-5-phosphate phosphogluconate - R-5-P: required for nucleotide biosynthesis
Pathway lipids (LLAATT; Glucose-6-phosphate
liver, lactating dehydrogenase NADPH functions:
mammaries, 1. Reductive biosynthesis of fatty acids and steroids
adrenals, adipose 2. Glutathione reduction inside RBCs
tissue, thyroid, 3. CYP450 monoxygenase system
testes) 4. Oxygen-dependent bactericidal mechanism of WBCs
5. Synthesis of Nitric Oxide

4|BIOC HEM
 GLUTATHIONE
- Reduced (G-SH) removes H2O2 in a reaction
(glutathione peroxidase)
- G-SH is regenerated by glutathione reductase which
requires NADPH

G6PD deficiency
- MOST COMMON disease producing enzyme
abnormality in humans
- ↓NADH in RBCS and ↓glutathione reductase activity →
dree radicals and peroxides accumulate
- Most common precipitating factor: Infections
- Pathology:
1. Heinz Bodies
2. Bite Cells

FASTING
GLYCOGENOLYSIS - Few hours after meal
- Increased GLUCAGON
- MAIN SOURCE of blood glucose for the next 8-12
hours
GLUCONEOGENESIS - Within 4 hours after meal
LIPOLYSIS - Fatty acid oxidation → ketone bodies (Liver)
- ATP and NADH promote GLUCONEOGENESIS
- GLYCEROL: carbon source for gluconeogenesis
20 hrs after meal GLUCONEOGENESIS = GLYCOGENOLYSIS
30 hrs after meal Glycogen is depleted, GLUCONEOGENESIS is the ONLY
SOURCE of blood glucose

PROLONGED FASTING (Starvation)

- Even after 5-6 weeks, glucose levels → 65 mg/dL
- Increased ketone bodies, brain uses ketones (35%) for energy needs
- Decreased rate of gluconeogenesis and urea production by the liver
- Muscle protein is spared

5|BIOC HEM
LIPIDS

Lipoproteins
1. Chylomicrons – produced in intestinal cells from dietary lipid
2. VLDL – liver, mainly from dietary carbohydrates
**TAG of chylomicrons and VLDL are hydrolyzed in the blood by lipoprotein lipase to
fatty acids and glycerol. In adipose cells, fatty acids → TAG and stored’
3. IDL – consists of remains of VLDL after digestions of some TAG
o Either endocytosed by liver cells and digested by lysosomal enzymes
or converted to LDL by further digestion of TAG
4. LDL – major cholesterol carrier, undergoes endocytosis and lysosomal
digestion in liver and peripheral tissues
5. HDL – transfers proteins to CM and VLDL

ACTIVATION OF FATTY ACIDS

- A fatty acid must be converted to its activated form before it can participate in
metabolic processes
- ENZYME: Fatty acyl Coa synthetase
- Occurs in CYTOSOL

Sphingolipids contain ceramide + variety of groups attached

1. Sphingomyelin contains phosphocholine
2. Cerebrosides contain sugar residue
3. Gangliosides contain a number of sugar residues (one of which is sialic acid)

6|BIOC HEM
 PROCESS LOCATION SUBSTRATE, END PRODUCTS RATE LIMITING STEP IMPORTANT NOTES
LIPOGENESIS Liver, kidney, S: acetyl CoA Acetyl Coa + HCO3- + ATP → - Synthesis of fatty acids (palmitate)
brain, lung, P: palmitoyl CoA Malonyl CoA - Glucose → liver (glycolysis) → pyruvate → Acetyl
mammary gland, CoA (pyruvate dehydrogenase) + Oxaloacetate
adipose Acetyl CoA Carboxylase (pyruvate carboxylase) → citrate (acetyl Coa
cannot cross mitochondrial membrane)
CYTOSOL - NADPH supplies reducing equivalents that occur on
the fatty acid synthase complex (produced by PPP,
malic enzyme, isocitrate dehydrogenase)
- Acetyl CoA supplies carbons for FA synthesis

Important Steps
1. Transport of Acetyl CoA (citrate shuttle) to cytosol
2. Formation of Malonyl CoA
- Enzyme: Acetyl CoA carboxylase (Coenzyme:
biotin)
- Inhibited by GLUCAGON and EPINEPHRINE
- Enzyme activated by DEPHOSPHORYLATION,
CITRATE, induced by INSULIN
- Malony CoA inhibits carnitine acyltransferase I →
prevents newly synthesized FA from entering
mitochondria and undergoing B-oxidation
3. Elongation to Palmitoyl CoA
- Primer: Acetyl CoA
- All subsequent carbon units added via Malonyl CoA
- Sequence (Condensation → Reduction → DHN →
Reduction) repeated 7 times
- NADPH is required as donor of reducing equivalents
in both reduction reactions
4. Further Elongation and Desaturation
- SER, FA may undergo:
a. Further elongation: very LCFA
b. Desaturation: double bonds up to Carbon 9
• In humans, double bonds at position 5,6,9
• Linoleate and a-linoleate are the major
sources of essential fatty acids; used for
synthesis of Arachidonic acid and other
PUFA

7|BIOC HEM
 Source of NADPH: PPP, Malic enzyme, Isocitrate
dehydrogenase
TAG synthesis 3 FAs are esterified into Synthesized by
glycerol-3-phosphate 1. Sequential addition of 2 Fatty Acyl CoA to G3P
2. Removal of phosphate
3. Addition of 3rd fatty acyl CoA
Sources of G3P
1. DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (glycerol kinase) –
liver only

BETA-OXIDATION Mitochondria S: Palmitate Translocation of fatty acyl - Removal of acetyl CoA (enter TCA) fragments from
Muscle and liver E: 8 Acetyl CoA, 7 NADH, 7 CoA from the cytosol to the ends of fatty acids also yielding NADH and
FADH2 mitochondria FADH2 (enter ETC)
- Oxidation of fatty acid with an odd number of
Enzyme: carnithine- carbon atoms will yield acetyl CoA and a molecule
palmitoyl transferase of propionyl CoA
- Propionyl CoA → Succinyl CoA
- For LCFA (14-20): carnithine
- For VLCFA (> 20): peroxisomes
- Oxidation of unsaturated FAs require an additional
enzymes (3,2 enoyl-CoA Isomerase)

Sequential enzymes:
- Propionyl CoA carboxylase requires Biotin
- Methylmalonyl CoA mutase requires Vitamin B12

Degradation sequence (7 times)

- Oxidation → Hydration → oxidation → thiolysis
-

8|BIOC HEM
 Fatty Acid Oxidase
- Fatty acyl CoA dehydrogenase
- Δ2 enol CoA hydratase
- 3-hydroxyacyl-CoA dehydrogenase
- Thiolase

ATP Yield of Plamitate

7 NADH 17.5
7 FADH2 10.5
8 Acetyl CoA 80
Activation -2
NET YIELD 106

KETOGENESIS Liver S: Acetyl CoA Acetoacetyl CoA + Acetyl Synthesis of ketone bodies which serve as alternative fuel
Mitochondria E: Acetoacetate, B- CoA → HmG CoA for peripheral tissues
hydroxybutyrate, Acetone
HmG CoA Synthase
KETOLYSIS Mitochondria of LIVER DO NOT USE KETONE BODIES AS FUEL BECAUSE IT
extrahepatic LACKS SUCCINYL COA-ACETOACETATE-COA
tissues (skeletal TRANSFERASE (thiophorase)
and cardiac
muscle, kidney,
intestines, brain)

9|BIOC HEM
 CHOLESTEROL All tissues HMG CoA → Mevalonate - Stored as cholesteryl esters
SYNTHESIS Most important:
liver, intestine, HMG CoA Reductase Regulation
adrenal cortex, Requires 2 NADPH 1. Product inhibition
ovaries, testes, - Cholesterol and metabolites repress transcription
placenta HMG-CoA reductase via activation of a sterol
regulatory element binding protein (SREBP) TF
Cytosol 2. Phosphorylation (inactivates) and
ER dephosphorylation (activates)
3. Hormonal regulation of HmG CoA reductase
- Increased by INSULIN/THYROID HORMONE
- Decreased by GLUCAGON/GLUCOCORTICOIDS

CHOLESTEROL is 95% reabsorbed in

the TERMINAL ILEUM

10 | B I O C H E M
 Aldo Corti Sex
21 a hydroxylase def
Most Common
HYPOTENSION, HYPERKALEMIA
↓ ↓ ↑
Increases renin, volume depletion
Masculinization, pseudohermaphroditism
Early virilization in males
11 b hydroxylase def
↓ aldo
Fluid retention (increased deo), low renin HTN ↓ ↑
↑ deo
Masculinization and virilization
17 a hydroxylase def
Hypertension, Hypokalemia
↑ ↓ ↓
Males: pseudohermaphroditism
Females: lack 2nd sex characteristics

INCREASING DENSITY
CM < VLDL < IDL < LDL < HDL

11 | B I O C H E M
 PROTEINS GLUTAMINE ASPARAGINE: site for N-linked glycosylation of proteins
GLUTAMINE: deaminated by glutaminase → ammonia; major carrier
of nitrogen from liver to peripheral tissues
CYSTEINE Contains sulfhydryl group
Participates in biosynthesis of coenzyme A
2 cysteines connected by disulfide bond → CYSTINE
Keratin contains a lot of Cystine

ACIDIC AMINO ACIDS

ASPARTATE Proton donors
GLUTAMATE Glutamate is the precursor of GABA and glutathione

BASIC AMINO ACIDS

Proton acceptors
HYDROPHOBIC HYDROPHILIC
At neutral pH: Arginine and Lysine are + charged; Histidine (weak base), no charge
Aromatic Side chains: Phenylalanine, Positively charged R goups: Lys, Arg, His
HISTIDINE Precursor of histamine
Tyrosine, Tryptophan Negtaively charged R groups: Asp, Glu
Used in diagnosis of folic acid deficiency (FIGlu excetion test)
Nonpolar Alipathic: Gly, Arg, Val, Leu, Ile, Polar, Uncharged R groups: Ser, Thr, Cys,
Concetration in brain hypothalamus varies with circadian rhythm
Pro Met, Asn, Gln
ARGININE Precursor of creatinine, urea, nitric oxide
LYSINE Precursor of Carnitine
NON POLAR AMINO ACIDS
GLYCINE Smallest side chain
ESSENTIAL AMINO ACIDS (Cannot be synthesized and are provided from dietary source)
Used in the first step of HEME synthesis - ARGININE IS REQUIRED ONLY DURING PERIODS of GROWTH or POSITIVE NITROGEN BALANCE
Used in synthesis of purines and creatinine PVT TIM HALL
Major inhibitory NT in the SC - Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Arginine, Lysine, Leucine
Conjugated to bile acids, drugs and other metabolites - CYSTINE AND TYROSINE can be synthesized in the body but ONLY from essential AA
Except for this AA, all are chiral
ALANINE Carrier of ammonia and of the carbons of pyruvate from skeletal SELENOCYSTEINE (21st amino acid)
muscle to liver
Nitrogen Balance
VAL, ILE, LEU Branched chain amino acids whose metabolites accumulate in MSUD NEGATIVE Loss > incorporated
PHENYLALANINE Accumulates in phenylketonuria Malnutrition (Kwashiorkor), Dietary Deficiency, Starvation, Uncontrolled diabetes, Infection
Precursor of tyrosine POSITIVE Incorporated > loss
TRYPTOPHAN Largest side chain Growth, Pregnancy, Convalescence, Recovery
Precursor of niacin, serotonin, melatonin
METHIONINE Source of methyl groups in metabolism Michaelis-Menten Equation
Part of S-adenosylmethionine (SAM) - Rate of reaction depends on both the CONCENTRATION OF ENZYME and SUBSTRATE which forms
product
Precursor of homocysteine and cysteine
- To increase Vmax, increase the [E]
PROLINE IMINO acid - When comparing enzymes, the one with higher Km has a lower affinity for its substrate
Contributes to the fibrous structure of collagen and interrupts a- - The Km value is an intrinsic property of the enzyme-substrate system and cannot be altered by
helices in globuar proteins changing [S] or [E]
- Competitive inhibitors increases Km
UNCHARGED POLAR AMINO ACIDS - Noncompetitive inhibitors decreases Vmax
SERINE Contain polar hydroxyl group
THREONINE Site for O-lnked glycosylation and phosphorylation of proteins
TYROSINE TYROSINE is a precursor of several compounds inc. thyroxine and
melanin
ASPARAGINE Has carbonyl and amide group

12 | B I O C H E M
AMINO ACID CATABOLISM
First Phase
- Deamination (removal of a-amino group) → ammonia and a-keto acid
- Ammonia may be excreted as Free Ammonia in urine and stool, but majority is converted to UREA
- Step 1: Transamination
o Transferring a-amino group to a-ketoglutarate → Formation of Glu
o Exceptions: Lysine, Threonine, Proline, Hydroxyproline
o Enzyme: aminotransferase
o Coenzyme: B6
- Step 2: Oxidative Deamination
o Enzyme: Glutamate dehydrogenase
o In liver and kidney, glutamate is oxidatively deaminated to release free ammonia Transport of Ammonia from Peripheral Tissues
Second Phase THROUGH GLUTAMINE
- A- keto acids → intermediates for Glycolysis and Krebs Cycle - Glutamate + Ammonia → Glutamine (glutamine synthetase)
- Glutamine is transported in the blood and may be deaminated to release ammonia:
Excretion of Excess Nitrogren o LIVER: in response to high protein intake
1. Ammotelic: telostean fish, ammonia o KIDNEYS: in response to metabolic acidosis
2. Uricotelic: birds, uric acid a semisolid guano THROUGH ALANINE
3. Ureotelic: land animals, urea - MUSCLE: pyruvate is transaminated to alanine
- Alanine is transported to liver where it is converted back to pyruvate

PROCESS LOCATION SUBSTRATE, END PRODUCTS RATE LIMITING STEP IMPORTANT NOTES
UREA CYCLE Liver S: NH3, aspartate, CO2 NH3 + CO2 → Carbamoyl - Synthesis of 1 mol of urea requires 3 mol of ATP
Mitochondria and E: Urea phosphate - N-acetylglutamate functions solely as an enzyme activator and
Cytosol regulates urea synthesis
Carbamoyl phosphate synthetase I
Allosteric Activator: N- Fates of urea
acetylglutamate - Transported in the blood to the kidneys for excretion in the
urine
- Some of the urea diffuses into the intestines, where urease-
Orange Ornithine positive bacteria convert them to CO2 and NH3
Colored Carbamoyl phosphate
Cat Citrulline
Always Aspartate
Ask Arginosuccinate
For Fumarate
An Arginine
Umbrella Urea

13 | B I O C H E M
 HEME METABOLISM Cytosol and S: Succinyl CoA + glycine Succinyl CoA + Glycine → δ- Porphyrins
Mitochondria E: Heme aminolevulinic Acid - Cyclic compounds formed by the linkage of four pyrrole rings
thru methyne (-HC) bridges
In almost all tissues ALA synthase - Form complexes with metal ions bound to the nitrogen atom
First and last 3 steps Cofactor: B6 of the pyrrole rings
occur in the
mitochondria Steps
1. δ-aminolevulinic Acid synthesis
2. Porphibilinogen is formed
- Condensation of 2 molecules of ALA by zinc containing ALA
dehydratase
- Inhibited by heavy metal ions that replace the zinc
3. 4 pBGs → uroporphyrinogen
4. Porphyrins are decarboxylated and oxidized
5. Protoporphyrin IX binds iron → Heme
- Fe 2+, enhanced by ferrochelatase; inhibited by lead
- VITAMIN C increases uptake of iron in intestinal tract
- CERLOPLASMIN is involved in the oxidation of iron
HEME DEGRADATION Steps
1. Bilirubin formation
- Heme → biliverdin (green) → bilirubin (red orange)
- Enzyme: heme oxygenase (release CO)
2. Uptake of bilirubin by the liver
- Bilirubin binds with albumin → liver
- In liver, bilirubin binds to intracellular protein (ligandin)
3. Formation of bilirubin diglucuronide
- Bilirubin is conjugated to 2 molecules of glucuronic acid
- Enzyme: Bilirubin glucuronyltransferase
- Deficient in Crigler-Najjar I and II, Gilbert Syndrome
4. Secretion of Bilirubin into bile
- Susceptible to impairment in liver disease
5. Formation of urobilins in the intestine
- GUT: bilirubin → urobilinogen (colorless)
- Intestinal bacteria then oxidize urobilinogen → stercobilin
(brown)
- Some urobilinogen is reabsorbed from the blood → portal
circulation
- Kidney: urobilinogen → urobilin (yellow)

14 | B I O C H E M
Synthesis of Non-Essential AA

Specialized Products

15 | B I O C H E M