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MBBS Biochemistry - Complete Topic Guide

Based on Lippincott Illustrated Reviews: Biochemistry (8e), Basic Medical Biochemistry: A Clinical Approach (6e), and Harper's Illustrated Biochemistry (32e)

UNIT 1: BIOMOLECULES

1. Amino Acids

20 standard amino acids are the only ones encoded by DNA. All share a central α-carbon bonded to: a carboxyl group (-COOH), an amino group (-NH₂), a hydrogen atom, and a unique side chain (R group).

At physiologic pH (~7.4):

The carboxyl group is dissociated → -COO⁻ (negatively charged)
The amino group is protonated → -NH₃⁺ (positively charged)

Classification by R group:

Class	Examples	Property
Nonpolar / Hydrophobic	Gly, Ala, Val, Leu, Ile, Pro, Phe, Trp, Met	Cluster in protein interior (hydrophobic effect)
Polar uncharged	Ser, Thr, Cys, Tyr, Asn, Gln	Hydrogen bond donors/acceptors
Positively charged (basic)	Lys, Arg, His	Protonated at physiologic pH
Negatively charged (acidic)	Asp, Glu	Deprotonated at physiologic pH

Essentials (mnemonic - PVT TIM HALL): Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys - these cannot be synthesized and must come from diet.

Zwitterion & pKa: Every amino acid has at least two pKa values (for α-COOH and α-NH₃⁺). At the isoelectric point (pI), the net charge = 0.

2. Protein Structure

Four levels of organization:

Primary: Sequence of amino acids linked by peptide bonds (covalent). Determines all higher structure. Sequenced directly (Edman degradation) or inferred from DNA.
Secondary: Local folding patterns stabilized by hydrogen bonds between backbone NH and C=O groups:
- α-helix: right-handed, 3.6 residues/turn, side chains point outward
- β-pleated sheet: parallel or antiparallel strands; found in silk, amyloid fibrils
- β-turns: connect β strands; proline and glycine are common here
Tertiary: Overall 3D shape of a single polypeptide. Stabilized by: hydrophobic interactions, disulfide bonds (-S-S-), ionic bonds, H-bonds, van der Waals forces
Quaternary: Association of two or more polypeptide chains. Example: hemoglobin (α₂β₂ tetramer)

Protein folding: Driven primarily by the hydrophobic effect. Chaperone proteins (e.g., Hsp70, chaperonins) assist folding and prevent misfolding. Misfolded proteins → aggregation → diseases (Alzheimer's, Parkinson's, prion diseases - all involve β-sheet-rich amyloid fibrils).

Fibrous proteins:

Collagen: Most abundant protein in the body. Triple helix of 3 polypeptide chains (Gly-X-Y repeats, where X = Pro, Y = hydroxyproline). Vitamin C is required for prolyl hydroxylase. Deficiency → scurvy (fragile capillaries, poor wound healing)
Elastin: Stretch and recoil in lungs, large arteries
Keratin: Hair, nails, skin

3. Hemoglobin and Myoglobin

Both are heme-containing proteins that bind O₂.

Feature	Myoglobin	Hemoglobin
Subunits	1 (monomer)	4 (α₂β₂ tetramer)
O₂ curve	Hyperbolic	Sigmoidal
Function	O₂ storage in muscle	O₂ transport in blood
Cooperativity	No	Yes (T→R state transition)

Hemoglobin allosteric regulation:

2,3-BPG: Binds deoxy-Hb (T state), decreases O₂ affinity → right-shifts curve → favors O₂ release to tissues
CO₂ and H⁺ (Bohr effect): Acidic pH and high CO₂ decrease O₂ affinity → O₂ released in metabolically active tissues
CO: Binds Hb with 200x greater affinity than O₂ → carbon monoxide poisoning

Hemoglobin variants:

HbS (Sickle cell): Glu → Val at position 6 of β-chain. Deoxygenated HbS polymerizes → sickle-shaped RBCs → hemolytic anemia, vaso-occlusive crises
HbA₁c: Glycated hemoglobin - used to monitor long-term blood glucose control (reflects average glucose over ~3 months)
Methemoglobin: Fe²⁺ oxidized to Fe³⁺; cannot carry O₂; treated with methylene blue

UNIT 2: ENZYMES

4. Enzyme Structure and Function

Enzymes are biological catalysts that increase reaction rate without being consumed. They lower the activation energy (Ea) by providing an alternate reaction pathway.

Key concepts:

Active site: Specific region that binds substrate (induced fit model)
Holoenzyme = apoenzyme (protein) + cofactor/coenzyme
Cofactors: Metal ions (Zn²⁺, Fe²⁺, Mg²⁺)
Coenzymes: Organic molecules derived from vitamins - NAD⁺ (from niacin/B3), FAD (from riboflavin/B2), CoA (from pantothenic acid/B5), pyridoxal phosphate (from B6)
Prosthetic groups: Permanently bound coenzymes (e.g., FAD in succinate dehydrogenase)

Six enzyme classes:

Oxidoreductases - oxidation/reduction (e.g., LDH, alcohol dehydrogenase)
Transferases - transfer functional groups (e.g., aminotransferases)
Hydrolases - hydrolysis (e.g., lipase, protease)
Lyases - addition/removal without hydrolysis (e.g., aldolase)
Isomerases - structural rearrangement (e.g., phosphoglucose isomerase)
Ligases - join molecules using ATP (e.g., DNA ligase, acetyl-CoA carboxylase)

5. Enzyme Kinetics

Michaelis-Menten equation:

v₀ = (Vmax × [S]) / (Km + [S])

Km = substrate concentration at half-maximum velocity = measure of enzyme-substrate affinity (low Km = high affinity)
Vmax = maximum velocity when enzyme is fully saturated
Kcat (turnover number) = number of substrate molecules converted per enzyme per second

Lineweaver-Burk plot (double reciprocal):

x-intercept = -1/Km
y-intercept = 1/Vmax
Used to distinguish types of inhibition graphically

Inhibition:

Type	Vmax	Km	Mechanism
Competitive	Unchanged	Increased	Inhibitor binds active site, competes with S; overcome by ↑[S]
Noncompetitive	Decreased	Unchanged	Inhibitor binds allosteric site; not overcome by ↑[S]
Uncompetitive	Decreased	Decreased	Binds only ES complex
Irreversible	Permanently ↓Vmax	-	Covalent binding (e.g., aspirin → cyclooxygenase; organophosphates → acetylcholinesterase)

Allosteric regulation: Enzymes with multiple subunits. Allosteric activators → shift to R state (relaxed, active). Allosteric inhibitors → shift to T state (tense, inactive). Sigmoidal kinetics (not Michaelis-Menten).

UNIT 3: CARBOHYDRATE METABOLISM

6. Glycolysis

Location: Cytoplasm
Net reaction: Glucose → 2 Pyruvate + 2 ATP (net) + 2 NADH

10 reactions in 2 phases:

Energy Investment Phase (reactions 1-5): Glucose is phosphorylated and split

Reaction 1: Glucose → Glucose-6-phosphate (hexokinase/glucokinase; uses 1 ATP; irreversible)
Reaction 3: Fructose-6-P → Fructose-1,6-bisphosphate (phosphofructokinase-1/PFK-1; uses 1 ATP; rate-limiting step, irreversible)
Reaction 5: Aldolase splits fructose-1,6-bisphosphate → DHAP + G3P

Energy Generation Phase (reactions 6-10): 2 G3P converted to 2 pyruvate

Reaction 10: Phosphoenolpyruvate → Pyruvate (pyruvate kinase; irreversible)

Regulation of PFK-1 (key rate-limiting step):

Activated by: AMP, ADP, fructose-2,6-bisphosphate (F-2,6-BP) - signals low energy
Inhibited by: ATP, citrate - signals high energy

Fate of pyruvate:

Aerobic: → Acetyl-CoA (pyruvate dehydrogenase complex) → TCA cycle
Anaerobic: → Lactate (lactate dehydrogenase; regenerates NAD⁺)
Yeast: → Ethanol + CO₂

Anaerobic glycolysis: Net 2 ATP per glucose. Used by RBCs (no mitochondria), lens of eye, exercising muscle.

7. TCA Cycle (Krebs Cycle / Citric Acid Cycle)

Location: Mitochondrial matrix
Input: 1 Acetyl-CoA (2 carbons)
Output per turn: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂

8 reactions:

Acetyl-CoA + Oxaloacetate → Citrate (citrate synthase)
Citrate → Isocitrate (aconitase)
Isocitrate → α-Ketoglutarate + CO₂ (isocitrate dehydrogenase; rate-limiting; produces NADH)
α-Ketoglutarate → Succinyl-CoA + CO₂ (α-ketoglutarate dehydrogenase; produces NADH)
Succinyl-CoA → Succinate (succinyl-CoA synthetase; produces GTP)
Succinate → Fumarate (succinate dehydrogenase; produces FADH₂; in inner mitochondrial membrane)
Fumarate → Malate (fumarase)
Malate → Oxaloacetate (malate dehydrogenase; produces NADH)

Regulation: Inhibited by high energy state (NADH, ATP, succinyl-CoA). Activated by ADP, Ca²⁺.

Anaplerotic reactions: Reactions that replenish TCA intermediates (e.g., pyruvate → oxaloacetate via pyruvate carboxylase).

8. Oxidative Phosphorylation and Electron Transport Chain (ETC)

Location: Inner mitochondrial membrane

ETC complexes:

Complex I: NADH → ubiquinone (pumps 4H⁺)
Complex II: FADH₂ → ubiquinone (no H⁺ pumping - why FADH₂ yields less ATP)
Complex III: Ubiquinol → cytochrome c (pumps 4H⁺)
Complex IV: Cytochrome c → O₂ (pumps 2H⁺; final electron acceptor = O₂ → H₂O)

ATP synthase (Complex V): Uses proton gradient (chemiosmosis) to synthesize ATP from ADP + Pi.

ATP yield:

NADH: ~2.5 ATP
FADH₂: ~1.5 ATP
1 glucose (aerobic): ~30-32 ATP total

Important inhibitors:

Rotenone/amytal: Block Complex I
Antimycin A: Blocks Complex III
Cyanide, CO, azide: Block Complex IV (cytochrome c oxidase)
Oligomycin: Blocks ATP synthase
Dinitrophenol (DNP): Uncoupler - dissipates proton gradient as heat (once used as diet drug - lethal)

9. Gluconeogenesis

Location: Primarily liver, also kidney cortex
Function: Synthesize glucose from non-carbohydrate precursors
Precursors: Lactate, glycerol, alanine (amino acids)

4 unique gluconeogenesis reactions (bypass glycolysis irreversible steps):

Pyruvate → Oxaloacetate (pyruvate carboxylase; requires biotin/B7; in mitochondria)
OAA → Phosphoenolpyruvate (PEPCK; requires GTP)
Fructose-1,6-bisphosphate → Fructose-6-phosphate (fructose-1,6-bisphosphatase)
Glucose-6-phosphate → Glucose (glucose-6-phosphatase; in liver and kidney only - not muscle)

Cori cycle: Lactate produced in muscle and RBCs → liver → converted back to glucose → returned to muscle.

Regulation: Glucagon and cortisol stimulate gluconeogenesis; insulin inhibits it.

10. Glycogen Metabolism

Glycogen: Branched polymer of glucose (α-1,4 linkages in chains; α-1,6 linkages at branch points). Stored in liver (blood glucose regulation) and muscle (local energy).

Synthesis (Glycogenesis):

UDP-glucose is the activated donor
Glycogen synthase: elongates chain (adds to α-1,4 bonds)
Branching enzyme: creates α-1,6 branches

Breakdown (Glycogenolysis):

Glycogen phosphorylase: cleaves α-1,4 bonds → Glucose-1-phosphate
Debranching enzyme: removes α-1,6 branch points

Regulation:

Glucagon/epinephrine → ↑cAMP → activate PKA → phosphorylate and activate phosphorylase, inactivate glycogen synthase → promote breakdown
Insulin → promotes synthesis, inhibits breakdown

Glycogen storage diseases:

Disease	Deficient Enzyme	Tissue	Feature
Von Gierke (Type I)	Glucose-6-phosphatase	Liver/kidney	Severe hypoglycemia, lactic acidosis
Pompe (Type II)	α-1,4-glucosidase (lysosomal)	All tissues	Cardiomegaly, muscle weakness
Cori (Type III)	Debranching enzyme	Liver/muscle	Mild hypoglycemia
McArdle (Type V)	Muscle phosphorylase	Muscle	Exercise intolerance, myoglobinuria

11. HMP Shunt (Pentose Phosphate Pathway)

Location: Cytoplasm (especially liver, adrenal cortex, RBCs, mammary gland)

Oxidative phase (irreversible):

Glucose-6-P → Ribulose-5-P
Produces: 2 NADPH + CO₂
Key enzyme: Glucose-6-phosphate dehydrogenase (G6PD)

Non-oxidative phase (reversible): Produces ribose-5-phosphate for nucleotide synthesis

Products and functions:

NADPH: Required for fatty acid synthesis, cholesterol synthesis, steroid synthesis, and most importantly - regeneration of glutathione (protects RBCs from oxidative damage)
Ribose-5-phosphate: Nucleotide and nucleic acid synthesis

G6PD deficiency: Most common enzyme deficiency worldwide (X-linked). RBCs cannot regenerate NADPH → cannot protect against oxidative stress → hemolytic anemia triggered by oxidants (primaquine, dapsone, fava beans). Heinz bodies (denatured hemoglobin) appear in RBCs.

12. Pyruvate Dehydrogenase Complex (PDC)

Connects glycolysis to TCA cycle.
Reaction: Pyruvate → Acetyl-CoA + CO₂ + NADH
Location: Mitochondrial matrix
Irreversible reaction

Cofactors (mnemonic - Tender Loving Care For Nancy):

TPP (thiamine/B1) - E1 (pyruvate decarboxylase)
Lipoic acid - E2 (dihydrolipoyl transacetylase)
CoA - E2
FAD - E3 (dihydrolipoyl dehydrogenase)
NAD⁺ - E3

Regulation:

Inhibited by: Acetyl-CoA, NADH, ATP (products signal "energy rich")
Activated by: CoA, NAD⁺, AMP, Ca²⁺

PDC deficiency: Leads to buildup of pyruvate → converted to lactate and alanine → lactic acidosis + neurological defects. Treatment: high fat, low carbohydrate diet; thiamine supplementation.

Arsenic poisoning: Inhibits lipoic acid → blocks PDC.

UNIT 4: LIPID METABOLISM

13. Fatty Acid Structure and Nomenclature

A fatty acid = hydrophobic hydrocarbon chain + terminal carboxyl group (pKa ~4.8).
At physiologic pH: -COO⁻ (deprotonated).

Naming: C₁₆:₀ = palmitic acid (16 carbons, 0 double bonds). C₁₈:₁Δ⁹ = oleic acid.

Essential fatty acids (cannot be synthesized - lack enzymes for Δ12 and Δ15 desaturation):

Linoleic acid (ω-6, 18:2) - precursor to arachidonic acid
α-Linolenic acid (ω-3, 18:3) - precursor to EPA, DHA

Arachidonic acid → prostaglandins, thromboxanes, leukotrienes (eicosanoids).

14. Fatty Acid Oxidation (β-Oxidation)

Location: Mitochondrial matrix
Activation: Fatty acid → Fatty acyl-CoA (by acyl-CoA synthetase; uses 2 ATP equivalents)
Transport: Long-chain fatty acids need carnitine carrier to cross inner mitochondrial membrane (carnitine palmitoyltransferase I = CPT-I - rate-limiting step)

Each cycle of β-oxidation removes 2 carbons as acetyl-CoA and produces:

1 NADH
1 FADH₂
1 Acetyl-CoA

For palmitate (C16:0): 7 cycles → 8 acetyl-CoA + 7 NADH + 7 FADH₂ → ~106 ATP net

Odd-chain fatty acids: Last 3 carbons → propionyl-CoA → methylmalonyl-CoA → succinyl-CoA (enters TCA). Requires vitamin B12.

Unsaturated FA: Require additional enzymes (enoyl-CoA isomerase; 2,4-dienoyl-CoA reductase requires extra NADPH).

Inhibition by malonyl-CoA: When FA synthesis is active (fed state), malonyl-CoA inhibits CPT-I to prevent futile cycling.

15. Ketone Body Metabolism

Synthesis (Ketogenesis):

Occurs in liver mitochondria during fasting, starvation, prolonged exercise, uncontrolled diabetes
Acetyl-CoA → Acetoacetate → β-hydroxybutyrate (and acetone, spontaneously)
Rate-limiting enzyme: HMG-CoA synthase (mitochondrial)

Utilization:

By brain, heart, skeletal muscle (liver CANNOT use its own ketone bodies - lacks succinyl-CoA transferase)
β-hydroxybutyrate → Acetoacetate → Acetoacetyl-CoA → 2 Acetyl-CoA → TCA

Diabetic ketoacidosis (DKA): Insulin deficiency → uncontrolled lipolysis → massive ketone production → metabolic acidosis + "fruity breath" (acetone)

16. Fatty Acid Synthesis

Location: Cytoplasm
Requires: NADPH (from HMP shunt), malonyl-CoA, acetyl-CoA, CO₂, biotin
Enzyme: Fatty acid synthase (FAS) - multifunctional enzyme complex

Steps: Acetyl-CoA (starter) + repeated addition of malonyl-CoA (2C extension) → palmitate (C16:0)

Rate-limiting step: Acetyl-CoA → Malonyl-CoA (by acetyl-CoA carboxylase / ACC; requires biotin)

ACC regulation:

Activated by: Citrate (signals excess acetyl-CoA), insulin
Inhibited by: Palmitoyl-CoA (end product), glucagon, epinephrine

17. Cholesterol Metabolism

Synthesis: All nucleated cells; primarily liver and intestine
Pathway: Acetyl-CoA → HMG-CoA → Mevalonate → ... → Cholesterol
Rate-limiting enzyme: HMG-CoA reductase (target of statins - e.g., lovastatin, atorvastatin)

Regulation of HMG-CoA reductase:

Inhibited by: Statins, high intracellular cholesterol, glucagon
Activated by: Insulin

Cholesterol functions:

Component of cell membranes (modulates fluidity)
Precursor to: Bile acids, steroid hormones (cortisol, aldosterone, sex hormones), vitamin D

Lipoproteins (transport cholesterol/lipids in blood):

Lipoprotein	Made in	Carries	Key Apoprotein
Chylomicrons	Intestine	Dietary TAG	ApoB-48
VLDL	Liver	Endogenous TAG	ApoB-100
IDL	Circulation	Remnant	ApoB-100
LDL	Circulation	Cholesterol to tissues	ApoB-100
HDL	Liver/intestine	Reverse cholesterol transport	ApoA-I

LDL receptor: Mediates uptake of LDL. Deficiency → Familial hypercholesterolemia → premature atherosclerosis, xanthomas.

UNIT 5: AMINO ACID METABOLISM

18. Protein Digestion and Amino Acid Absorption

Stomach: Pepsin (active at pH 1-2) → oligopeptides
Pancreas: Trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidases (zymogens activated in duodenum)
Trypsin: Cleaves after Arg, Lys; trypsinogen → trypsin activated by enteropeptidase (from duodenum)
Brush border: Aminopeptidases, dipeptidases complete digestion
Absorption: Free amino acids and di/tripeptides via sodium-dependent cotransporters

19. Transamination and Deamination

Transamination: Transfer of α-amino group from an amino acid to an α-keto acid (usually α-ketoglutarate → glutamate). Requires pyridoxal phosphate (B6).

ALT (SGPT): Alanine + α-KG → Pyruvate + Glutamate (liver-specific; elevated in hepatocellular damage)
AST (SGOT): Aspartate + α-KG → OAA + Glutamate (liver, heart, muscle)

Oxidative deamination: Glutamate → α-ketoglutarate + NH₄⁺ (by glutamate dehydrogenase; in liver; reversible; uses NAD⁺ or NADP⁺)

20. Urea Cycle

Location: Liver (enzymes split between mitochondria and cytoplasm)
Function: Dispose of toxic NH₄⁺ as urea (non-toxic, water-soluble, excreted in urine)

Steps:

NH₄⁺ + CO₂ + 2ATP → Carbamoyl phosphate (CPS-I; in mitochondria)
Carbamoyl phosphate + Ornithine → Citrulline (OTC; in mitochondria)
Citrulline + Aspartate → Argininosuccinate (argininosuccinate synthetase; in cytoplasm; uses ATP)
Argininosuccinate → Arginine + Fumarate (argininosuccinate lyase)
Arginine → Ornithine + Urea (arginase)

Key points:

1 urea = 2 nitrogen atoms (1 from NH₄⁺ via CPS-I, 1 from aspartate)
Costs 4 ATP equivalents per urea
Hyperammonemia → cerebral edema, altered consciousness (NH₃ is neurotoxic)

Urea cycle disorders:

OTC deficiency (most common; X-linked) → hyperammonemia, ↑orotic acid in urine
CPS-I deficiency → hyperammonemia, normal orotic acid (no orotic acid accumulation)

21. Amino Acid Catabolism - Glucogenic vs Ketogenic

Glucogenic AAs (carbon skeleton → pyruvate or TCA intermediates → gluconeogenesis): Ala, Gly, Ser, Thr, Cys, Met, Val, Ile, Asp, Asn, Glu, Gln, Pro, Arg, His

Ketogenic AAs (→ acetyl-CoA or acetoacetate → ketone bodies, NOT glucose):

Purely ketogenic: Lys, Leu (mnemonic: Lucky Leu)
Both: Ile, Phe, Tyr, Trp, Lys

Phenylketonuria (PKU): Phenylalanine hydroxylase deficiency → Phe accumulates → converted to phenylketones → intellectual disability if untreated. Treat with Phe-restricted diet + tetrahydrobiopterin (BH4) if BH4-deficiency PKU. Newborn screening at birth.

Maple Syrup Urine Disease (MSUD): Branched-chain α-keto acid dehydrogenase deficiency → Val, Leu, Ile accumulate → sweet-smelling urine, encephalopathy.

Alkaptonuria: Homogentisate oxidase deficiency → homogentisate accumulates → dark urine, ochronosis (dark pigment in connective tissue), arthritis.

Homocystinuria: Cystathionine β-synthase deficiency (B6-dependent) OR methyleneTHF reductase deficiency (B12, folate) → homocysteine accumulates → lens dislocation, DVT, intellectual disability, cardiovascular disease.

22. One-Carbon Metabolism and Folate/B12

Tetrahydrofolate (THF): Carries one-carbon units at various oxidation states. Essential for:

Purine synthesis (C2 and C8 of purine ring)
dTMP synthesis (thymidylate synthase: dUMP → dTMP)
Regeneration of methionine from homocysteine

Vitamin B12 (cobalamin): Required for:

Methionine synthesis (homocysteine + methyl-THF → methionine; releases THF)
Conversion of methylmalonyl-CoA → succinyl-CoA

Folate trap: B12 deficiency traps folate as methyl-THF → functional folate deficiency → megaloblastic anemia (macrocytic, no neurological damage). B12 deficiency also causes subacute combined degeneration of spinal cord (demyelination of dorsal and lateral columns → loss of proprioception, vibration, UMN signs).

Methotrexate, trimethoprim: Inhibit dihydrofolate reductase → block THF regeneration → ↓dTMP → impair cell division (used as anticancer/antibacterial agents).

UNIT 6: NUCLEOTIDE METABOLISM

23. Purine Metabolism

De novo synthesis: Built on ribose-5-phosphate scaffold (from HMP shunt). Starts with PRPP (phosphoribosyl pyrophosphate). Produces IMP → AMP or GMP.
Requires: Glutamine, glycine, aspartate, N¹⁰-formyl-THF, CO₂

Salvage pathway: Recycles free purines (more energy-efficient). Key enzymes:

HGPRT (hypoxanthine-guanine phosphoribosyltransferase): Converts hypoxanthine → IMP, guanine → GMP

Purine catabolism: AMP → IMP → hypoxanthine → xanthine → uric acid (by xanthine oxidase)

Gout: Hyperuricemia → monosodium urate crystals → acute arthritis (first MTP joint = podagra), tophi, uric acid nephrolithiasis.

Allopurinol: Inhibits xanthine oxidase (used for chronic gout)
Colchicine: Inhibits microtubule polymerization → reduces neutrophil migration (acute gout)

Lesch-Nyhan syndrome: HGPRT deficiency (X-linked) → cannot salvage purines → purines degraded to uric acid → severe gout + self-mutilation + intellectual disability + choreoathetosis.

Adenosine deaminase (ADA) deficiency: Deoxyadenosine accumulates → toxic to lymphocytes → severe combined immunodeficiency (SCID).

24. Pyrimidine Metabolism

De novo synthesis: Ring assembled first (unlike purines). Starts with: CO₂ + glutamine + aspartate → orotate → UMP → UDP → UTP → CTP. Requires: CPS-II (cytoplasmic; uses glutamine, unlike CPS-I which uses NH₄⁺)

Pyrimidine catabolism: → β-amino acids (not uric acid) → not affected by gout.

Orotic aciduria: Deficiency of UMP synthase → orotic acid accumulates in urine → megaloblastic anemia that does NOT respond to B12 or folate. Treat with uridine.

Orotic aciduria with hyperammonemia → OTC deficiency (urea cycle)
Orotic aciduria without hyperammonemia → UMP synthase deficiency (pyrimidine synthesis)

UNIT 7: MOLECULAR BIOLOGY

25. DNA Structure and Replication

DNA double helix:

Two antiparallel strands
Base pairing: A=T (2 H-bonds), G≡C (3 H-bonds) → GC-rich DNA has higher melting temperature (Tm)
Helical turns every 10 base pairs (B-form DNA)
Supercoiling relaxed by topoisomerases (Type I: cleaves 1 strand; Type II: cleaves both strands - target of quinolones in bacteria, etoposide in cancer)

Semiconservative replication: Each daughter cell gets one old strand + one new strand.

Prokaryotic replication:

Origin: oriC (single origin)
Primase → RNA primer
DNA pol III: Major polymerase (5'→3' synthesis, 3'→5' proofreading exonuclease)
DNA pol I: Removes RNA primer, fills gap
DNA ligase: Seals nicks

Eukaryotic replication:

Multiple origins of replication
DNA pol α (primase), δ (lagging strand), ε (leading strand)
Telomerase: Adds TTAGGG repeats to chromosome ends (uses RNA template = reverse transcriptase)
Telomere shortening → cellular senescence; telomerase reactivation → cancer

26. Transcription (RNA Synthesis)

Prokaryotic RNA polymerase: Single enzyme, σ factor for promoter recognition, rifampicin inhibits it.

Eukaryotic RNA polymerases:

RNA pol I: rRNA (large ribosomal RNAs)
RNA pol II: mRNA (and snRNA); inhibited by α-amanitin (Amanita phalloides mushroom toxin)
RNA pol III: tRNA and 5S rRNA

mRNA Processing (eukaryotes only):

5' 7-methylguanosine cap: Added co-transcriptionally; protects from degradation, aids ribosome binding
3' poly-A tail: Added by poly-A polymerase; ~200 adenine residues; enhances stability
Splicing: Snurps (snRNPs) form the spliceosome; remove introns, join exons. Splice sites: GU...AG (GT-AG rule in DNA)

Alternative splicing: One gene → multiple protein isoforms

27. Translation (Protein Synthesis)

Genetic code:

64 codons (4³)
61 code for amino acids + 3 stop codons (UAA, UAG, UGA - "U Are Away," "U Are Gone," "U Go Away")
Degenerate/redundant: Multiple codons → same amino acid
Unambiguous: Each codon → only one amino acid
Nearly universal across all life forms

Ribosomes: 70S (prokaryotes: 50S + 30S); 80S (eukaryotes: 60S + 40S)

Translation steps:

Initiation: Met-tRNA binds start codon (AUG) at P site; requires initiation factors, GTP
Elongation: Codon-anticodon recognition at A site → peptide bond formation (peptidyl transferase = 23S rRNA - ribozyme) → translocation. Requires EF-Tu (GTP) and EF-G (GTP)
Termination: Stop codon → release factors → polypeptide released

Antibiotic targets (clinically vital):

Antibiotic	Target	Action
Aminoglycosides	30S	Misreading of mRNA
Tetracyclines	30S	Block aminoacyl-tRNA binding
Chloramphenicol	50S	Inhibits peptidyl transferase
Macrolides (erythromycin)	50S	Block translocation
Linezolid	70S initiation	Blocks initiation complex

Diphtheria toxin: ADP-ribosylates EF-2 (eukaryotic) → blocks translocation → cell death.

UNIT 8: VITAMINS AND MINERALS

28. Fat-Soluble Vitamins (A, D, E, K)

Vitamin	Active Form	Function	Deficiency	Toxicity
A (Retinol)	Retinal, Retinoic acid	Vision (rhodopsin), epithelial differentiation, immune function	Night blindness, xerophthalmia, keratomalacia	Teratogenic, liver damage
D (Cholecalciferol)	1,25-(OH)₂D₃ (Calcitriol)	Ca²⁺ and phosphate absorption; bone mineralization	Rickets (children), Osteomalacia (adults)	Hypercalcemia
E (Tocopherol)	α-tocopherol	Antioxidant (protects membrane lipids)	Hemolytic anemia, ataxia, neuropathy	Rare
K (Phylloquinone)	Hydroquinone	γ-carboxylation of Glu in clotting factors (II,VII,IX,X, protein C, S)	Bleeding (newborns at risk - no gut flora)	Warfarin resistance

Vitamin D synthesis: Skin (7-dehydrocholesterol + UV) → Cholecalciferol → liver 25-hydroxylation → kidney 1α-hydroxylation → 1,25-(OH)₂D₃ (calcitriol; active form). PTH stimulates 1α-hydroxylase.

29. Water-Soluble Vitamins (B complex and C)

Vitamin	Active Form	Key Function	Deficiency
B1 (Thiamine)	TPP	PDC, α-KG dehydrogenase, transketolase	Beriberi (wet = cardiac failure; dry = peripheral neuropathy), Wernicke-Korsakoff (alcoholics)
B2 (Riboflavin)	FMN, FAD	Electron carrier in ETC, β-oxidation	Corneal vascularization, cheilosis, glossitis
B3 (Niacin)	NAD⁺, NADP⁺	Redox reactions (>500 enzymes); synthesized from Trp (requires B6)	Pellagra (4Ds: Diarrhea, Dermatitis, Dementia, Death)
B5 (Pantothenic acid)	CoA	Acyl carrier in fatty acid and TCA metabolism	Rare; "burning feet"
B6 (Pyridoxine)	Pyridoxal phosphate (PLP)	Transamination, decarboxylation, glycogen phosphorylase	Sideroblastic anemia, peripheral neuropathy, seizures
B7 (Biotin)	Biotin	Carboxylation reactions (ACC, PDC, pyruvate carboxylase)	Raw egg whites block absorption (avidin); dermatitis, alopecia
B9 (Folic acid)	THF	One-carbon transfer; neural tube development	Megaloblastic anemia; neural tube defects (spina bifida)
B12 (Cobalamin)	Methylcobalamin, Adenosylcobalamin	Myelin synthesis, methionine synthesis	Megaloblastic anemia + subacute combined degeneration; pernicious anemia (anti-intrinsic factor Ab)
C (Ascorbic acid)	Ascorbate	Collagen synthesis (prolyl hydroxylase), antioxidant, Fe absorption	Scurvy (perifollicular hemorrhage, bleeding gums, corkscrew hairs, impaired wound healing)

UNIT 9: HORMONES AND SIGNAL TRANSDUCTION

30. Hormone Mechanisms

Peptide/protein hormones (insulin, glucagon, FSH, LH, TSH, ACTH, GH):

Hydrophilic → cannot cross membrane
Bind surface receptors → second messengers (cAMP, IP₃/DAG, Ca²⁺)
Fast action; no gene transcription directly

cAMP pathway: Hormone → Gs protein → adenylyl cyclase → cAMP → PKA → phosphorylates target proteins

Glucagon, epinephrine (β-adrenergic), FSH, LH, TSH, ACTH, PTH, calcitonin use this pathway

IP₃/DAG pathway: Hormone → Gq → phospholipase C → IP₃ (→ Ca²⁺ release from ER) + DAG (→ PKC)

Epinephrine (α₁), oxytocin, ADH (V₁), angiotensin II use this pathway

Steroid/thyroid/vitamin D hormones:

Lipophilic → cross plasma membrane → bind intracellular/nuclear receptors → transcription factors → gene expression changes
Slow action (hours); longer duration

31. Insulin and Glucagon

Insulin (from β-cells of pancreatic islets of Langerhans):

Stimulated by: High blood glucose, amino acids (Arg, Lys), GIP, GLP-1, vagal stimulation
Receptor: Tyrosine kinase receptor
Actions: ↑Glucose uptake (GLUT-4 in muscle/fat), ↑glycogen synthesis, ↑FA synthesis, ↑protein synthesis, ↓gluconeogenesis, ↓lipolysis, ↓ketogenesis

Glucagon (from α-cells):

Stimulated by: Low blood glucose, amino acids, epinephrine
Receptor: GPCR → cAMP → PKA
Actions: ↑Glycogenolysis (liver), ↑Gluconeogenesis, ↑Lipolysis, ↑Ketogenesis, opposes insulin

UNIT 10: INTEGRATION AND CLINICAL BIOCHEMISTRY

32. Metabolic States: Fed vs. Fasting vs. Starvation

State	Primary Fuel	Key Pathways Active
Fed	Glucose	Glycolysis, glycogen synthesis, FA synthesis, protein synthesis
Post-absorptive (overnight fast)	Glucose from glycogenolysis	Glycogenolysis (liver), begins gluconeogenesis
Short-term fasting (1-3 days)	Glucose (gluconeogenesis) + FA (β-oxidation)	Gluconeogenesis (liver), lipolysis, β-oxidation
Prolonged starvation (>1 week)	Ketone bodies (brain adapts)	Ketogenesis (liver), muscle protein catabolism slows

Glucose-alanine cycle (Cahill cycle): Muscle pyruvate + glutamate → alanine → blood → liver → transaminated back → pyruvate for gluconeogenesis + urea cycle.

33. Diabetes Mellitus - Biochemical Basis

Type 1 DM: Autoimmune destruction of β-cells → absolute insulin deficiency → uncontrolled lipolysis + ketogenesis → DKA (pH <7.3, high anion gap, ketonemia)

Type 2 DM: Insulin resistance + relative insulin deficiency → hyperglycemia. Less prone to DKA (some residual insulin suppresses ketogenesis). May develop hyperosmolar hyperglycemic state (HHS).

Chronic complications (due to hyperglycemia):

Polyol pathway: Glucose → Sorbitol (aldose reductase) → depletes NADPH → cataract, peripheral neuropathy, retinopathy
Non-enzymatic glycation: Glucose + protein → Amadori products → AGEs (advanced glycation end-products) → vessel damage → nephropathy, retinopathy
Protein kinase C activation → vascular damage

HbA1c reflects average blood glucose over ~3 months (reflects lifetime of RBC).

34. Plasma Proteins and Electrophoresis

Serum protein electrophoresis bands (anode to cathode): Albumin, α₁ (AAT, α₁-fetoprotein), α₂ (haptoglobin, ceruloplasmin, α₂-macroglobulin), β (transferrin, β-lipoprotein, C3), γ (immunoglobulins)

Albumin: Most abundant plasma protein (made in liver). Functions: Maintains oncotic pressure, transports FFA, bilirubin, drugs, hormones. Negative acute-phase reactant.

Acute-phase reactants:

Positive (increase in inflammation): CRP, fibrinogen, haptoglobin, ferritin, α₁-antitrypsin, ceruloplasmin
Negative (decrease): Albumin, transferrin

α₁-antitrypsin (AAT) deficiency: Cannot inhibit neutrophil elastase → lungs: emphysema; liver: cirrhosis (misfolded protein accumulates in hepatocytes, periodic acid-Schiff positive inclusions).

35. Porphyrin and Heme Metabolism

Heme synthesis:

Starts and ends in mitochondria; middle steps in cytoplasm
Succinyl-CoA + Glycine → ALA (δ-aminolevulinic acid; by ALA synthase; rate-limiting; requires PLP/B6)
ALA → porphobilinogen → ... → protoporphyrin IX + Fe²⁺ → Heme

Heme degradation:

Heme → Biliverdin → Bilirubin (unconjugated; lipid-soluble; transported bound to albumin)
Liver: Bilirubin + 2 glucuronate → Conjugated bilirubin (water-soluble; into bile)
Intestine: → Urobilinogen → stercobilin (stool color) / urobilin (urine)

Jaundice types:

Type	Bilirubin	Urine bilirubin	Urine urobilinogen	Cause
Pre-hepatic (hemolytic)	↑Unconjugated	Absent	↑	Hemolysis
Hepatic (hepatocellular)	Both ↑	Present	Variable	Hepatitis, cirrhosis
Post-hepatic (obstructive)	↑Conjugated	Present	Absent	Gallstones, pancreatic cancer

Porphyrias: Enzyme defects in heme synthesis → accumulation of porphyrin intermediates:

Acute Intermittent Porphyria (AIP): PBG deaminase deficiency; no skin manifestations; 5 P's: Pain (abdomen), Port wine urine, Polyneuropathy, Psychiatric symptoms, Precipitated by drugs/fasting; treat with IV glucose and hematin
Porphyria Cutanea Tarda (PCT): Uroporphyrinogen decarboxylase deficiency; skin fragility, blistering with sun exposure

Lead poisoning: Inhibits ALA dehydratase and ferrochelatase → ↑ALA and ↑protoporphyrin IX → microcytic hypochromic anemia, basophilic stippling, neurological damage (encephalopathy), Burton's lines on gums.

36. Acid-Base Balance - Biochemical Aspects

Henderson-Hasselbalch: pH = 6.1 + log([HCO₃⁻] / 0.03 × PCO₂)

Buffer systems:

Bicarbonate (most important extracellular): H₂CO₃ ↔ H⁺ + HCO₃⁻
Phosphate (intracellular)
Proteins (hemoglobin - major intracellular buffer in RBCs)

Carbonic anhydrase: CO₂ + H₂O ↔ H₂CO₃ in RBCs. Inhibited by acetazolamide (used in glaucoma, altitude sickness).

QUICK REFERENCE: HIGH-YIELD CLINICAL CORRELATIONS

Condition	Enzyme Defect	Key Feature
PKU	Phenylalanine hydroxylase	Musty odor, intellectual disability, fair skin
Albinism	Tyrosinase	No melanin, photosensitivity
Alkaptonuria	Homogentisate oxidase	Dark urine, ochronosis
Homocystinuria	CBS (B6) or MTHFR (B9/B12)	Lens dislocation upward (Marfan = down)
MSUD	BCKDH	Sweet/maple syrup urine
G6PD deficiency	G6PD	Hemolysis with oxidant stress
Von Gierke	Glucose-6-phosphatase	Severe hypoglycemia, hepatomegaly
Pompe	α-glucosidase	Cardiomegaly, "floppy baby"
Lesch-Nyhan	HGPRT	Gout + self-mutilation
Gaucher	Glucocerebrosidase	Bone pain, hepatosplenomegaly
Niemann-Pick	Sphingomyelinase	Cherry-red spot, foam cells
Tay-Sachs	Hexosaminidase A	Cherry-red spot, no organomegaly
Fabry	α-galactosidase A	Angiokeratomas, renal failure

Sources: Lippincott Illustrated Reviews: Biochemistry, 8e (ISBN 9781975155063) - Basic Medical Biochemistry: A Clinical Approach, 6e (ISBN 9781975150143) - Harper's Illustrated Biochemistry, 32e (ISBN 9781260469943)

This covers the complete MBBS Biochemistry curriculum across all major units. Each section links the biochemical mechanism to its clinical relevance - the approach most tested in university exams and NEET-PG/USMLE. If you want any topic expanded further with more detail, diagrams, or practice questions, just ask!

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