Enzymology biochemistry
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I now have comprehensive content from the textbooks. Here is the complete USMLE-focused guide:
Enzymology: Coenzymes, Cofactors & Enzyme Classification
1. Core Terminology (High-Yield)
| Term | Definition |
|---|---|
| Apoenzyme | Protein portion of an enzyme - inactive without its nonprotein component |
| Cofactor | Nonprotein component needed for enzyme activity |
| Holoenzyme | Apoenzyme + cofactor = the active, complete enzyme |
| Coenzyme | Small organic molecule cofactor (usually derived from a vitamin) |
| Prosthetic group | Coenzyme permanently (covalently) bound to the enzyme; does not dissociate |
USMLE pearl: Apoenzyme (inactive) + cofactor = Holoenzyme (active). A vitamin deficiency reduces the coenzyme pool, leaving inactive apoenzyme in cells.
- Biochemistry, 8th ed - Lippincott Illustrated Reviews, p.172
2. Cofactors vs. Coenzymes
Cofactor
├── Metal ion (Zn²⁺, Fe²⁺, Mg²⁺, Cu²⁺, Mn²⁺) ← "cofactor" strictly
└── Small organic molecule ← "coenzyme"
├── Cosubstrate: transiently binds, leaves altered (e.g., NAD⁺ → NADH)
└── Prosthetic group: permanently bound, regenerated in place (e.g., FAD, heme)
- Lippincott's Biochemistry, p.172; Basic Medical Biochemistry - A Clinical Approach 6e, p.241
3. The Two Classes of Coenzymes
A. Activation-Transfer Coenzymes
Form a covalent bond with part of the substrate, activating it for transfer.
| Coenzyme | Vitamin Source | Functional Group | What is Transferred | Key Enzymes |
|---|---|---|---|---|
| Thiamin pyrophosphate (TPP) | B1 (Thiamin) | Reactive carbanion carbon | Acyl groups (after decarboxylation) | Pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, transketolase |
| Coenzyme A (CoASH) | B5 (Pantothenate) | Sulfhydryl (-SH) group | Acyl groups (forms thioesters) | Acetyl-CoA carboxylase, citrate synthase, fatty acid synthase |
| Biotin | Biotin (B7) | CO₂ carrier via N atom | CO₂ (carboxylation reactions) | Pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase |
| Pyridoxal phosphate (PLP) | B6 (Pyridoxine) | Schiff base with amino acid | Amino groups (transamination) | Aminotransferases (AST, ALT), decarboxylases, synthases |
USMLE pearl - Biotin: Biotin is covalently attached to a lysine residue on its enzyme (biotin-lysine = biocytin), making it a prosthetic group. Avidin in raw egg whites binds biotin and causes deficiency.
USMLE pearl - PLP: PLP is the coenzyme for ALL transamination reactions and amino acid decarboxylases. Isoniazid (INH) depletes PLP, causing peripheral neuropathy - prevented with B6 supplementation.
B. Oxidation-Reduction Coenzymes
Do NOT form covalent bonds with substrate. They accept and donate electrons via their unique functional groups.
| Coenzyme | Vitamin Source | Electrons Transferred | Type | Key Enzymes/Pathways |
|---|---|---|---|---|
| NAD⁺ / NADH | B3 (Niacin) | Hydride ion (H⁻) = 2e⁻ | Cosubstrate (dissociates) | Glycolysis, TCA, beta-oxidation, LDH |
| NADP⁺ / NADPH | B3 (Niacin) | Hydride ion (H⁻) = 2e⁻ | Cosubstrate (dissociates) | Pentose phosphate pathway, fatty acid synthesis, steroid synthesis |
| FAD / FADH₂ | B2 (Riboflavin) | 2H atoms (2e⁻ + 2H⁺) | Prosthetic group (stays bound) | Succinate dehydrogenase, fatty acyl-CoA dehydrogenase, complex II |
| FMN / FMNH₂ | B2 (Riboflavin) | 2H atoms | Prosthetic group | Complex I (NADH dehydrogenase) |
| Coenzyme Q (Ubiquinone) | Not a vitamin | Single electrons | Lipid-soluble carrier | Electron transport chain (complex I, II → III) |
| Lipoic acid | Not a vitamin | Acyl groups + electrons | Prosthetic group | Pyruvate dehydrogenase complex, alpha-KG dehydrogenase |
| Vitamin C (Ascorbate) | C | Single electrons | Antioxidant/cosubstrate | Procollagen hydroxylase, dopamine beta-hydroxylase |
| Vitamin E (Tocopherol) | E | Single electrons | Antioxidant (membrane) | Protects polyunsaturated fatty acids from lipid peroxidation |
The diagram below shows NAD⁺ accepting a hydride ion from lactate (oxidation-reduction coenzyme in action):
Figure: NAD⁺ accepts a hydride ion (shown in red) from lactate, producing NADH + pyruvate. NADP⁺ has the same mechanism but adds a phosphate group at the 2' position of adenosine ribose. - Basic Medical Biochemistry 6e, p.246
USMLE pearl - NAD vs NADP: NAD⁺ is used in catabolism (fuel oxidation = energy generation). NADPH is used in anabolism (biosynthesis) and antioxidant defense (glutathione reductase in RBCs). G6PD deficiency impairs NADPH production, leaving RBCs vulnerable to oxidative hemolysis.
USMLE pearl - FAD vs NAD: FAD is a prosthetic group (stays on the enzyme); NAD⁺ is a cosubstrate (dissociates). This is why succinate dehydrogenase cannot be inhibited competitively like NAD-dependent enzymes.
4. Vitamin-to-Coenzyme Quick Reference (High-Yield Table)
| Vitamin | Active Coenzyme Form | Key Reaction Type | Deficiency Disease |
|---|---|---|---|
| B1 - Thiamin | TPP (thiamin pyrophosphate) | Oxidative decarboxylation of alpha-keto acids | Beriberi, Wernicke-Korsakoff |
| B2 - Riboflavin | FAD, FMN | Oxidation-reduction | Cheilosis, corneal vascularization |
| B3 - Niacin | NAD⁺, NADP⁺ | Oxidation-reduction | Pellagra (dermatitis, diarrhea, dementia) |
| B5 - Pantothenate | CoASH (Coenzyme A) | Acyl group transfer | Rare (burning feet syndrome) |
| B6 - Pyridoxine | PLP (pyridoxal phosphate) | Transamination, decarboxylation | Peripheral neuropathy, sideroblastic anemia |
| B7 - Biotin | Biocytin (biotin-lysine) | CO₂ fixation (carboxylation) | Dermatitis, alopecia (raw egg whites, antibiotic use) |
| B9 - Folate | THF, 5,10-methylene THF | One-carbon transfers | Megaloblastic anemia, neural tube defects |
| B12 - Cobalamin | Adenosylcobalamin, Methylcobalamin | Isomerization (MMA mutase), methylation (methionine synthase) | Megaloblastic anemia + subacute combined degeneration |
| C - Ascorbate | Ascorbate (active itself) | Hydroxylation of proline/lysine | Scurvy |
- Harper's Illustrated Biochemistry 32e, p.147-152; Basic Medical Biochemistry 6e, p.242-244
5. Enzyme Classification (IUB System)
The International Union of Biochemistry classifies all enzymes into 6 main classes based on the reaction they catalyze:
| Class | Name | Reaction Catalyzed | Coenzyme Often Used | Examples |
|---|---|---|---|---|
| 1 | Oxidoreductases | Oxidation-reduction (transfer e⁻) | NAD⁺, FAD, NADP⁺ | LDH, succinate dehydrogenase, alcohol dehydrogenase |
| 2 | Transferases | Transfer functional groups (-CH₃, -NH₂, -phosphate) | PLP, TPP, CoA | Aminotransferases (AST, ALT), kinases, methyltransferases |
| 3 | Hydrolases | Hydrolysis (bond cleavage by adding H₂O) | None typically | Proteases (pepsin, trypsin), lipases, phosphatases |
| 4 | Lyases | Breaking bonds without hydrolysis or oxidation; adds/removes groups | PLP, TPP | Aldolase, pyruvate decarboxylase, citrate synthase |
| 5 | Isomerases | Rearranging atoms within the same molecule | None typically | Phosphoglucose isomerase, mutases, epimerases |
| 6 | Ligases | Joining two molecules using ATP (C-C, C-O, C-N, C-S bonds) | Biotin (for CO₂ ligations) | Pyruvate carboxylase, acetyl-CoA carboxylase, DNA ligase |
Mnemonic: O T H L I L - "Oh The Hell Let It Live" (Oxidoreductases, Transferases, Hydrolases, Lyases, Isomerases, Ligases)
6. Metal Ion Cofactors (USMLE High-Yield)
| Metal Ion | Key Enzymes | Clinical Relevance |
|---|---|---|
| Zinc (Zn²⁺) | Carbonic anhydrase, alcohol dehydrogenase, carboxypeptidase, DNA polymerase | Zinc deficiency: poor wound healing, ageusia, alopecia |
| Iron (Fe²⁺/Fe³⁺) | Cytochromes, catalase, peroxidase, ribonucleotide reductase | Iron deficiency anemia; iron overload (hemochromatosis) |
| Copper (Cu²⁺) | Cytochrome c oxidase, superoxide dismutase, lysyl oxidase, dopamine beta-hydroxylase, tyrosinase | Menkes disease (Cu²⁺ transport defect); Wilson disease (Cu accumulation) |
| Magnesium (Mg²⁺) | Kinases (activates ATP-Mg complex), enolase, DNA/RNA polymerases | Required for nearly all phosphoryl transfer reactions |
| Selenium (Se) | Glutathione peroxidase | Protects against oxidative damage; Keshan disease (deficiency) |
| Molybdenum (Mo) | Xanthine oxidase | Allopurinol inhibits xanthine oxidase (gout treatment) |
7. Key USMLE High-Yield Points Summary
- Apoenzyme + cofactor = Holoenzyme. Vitamin deficiency leaves inactive apoenzyme.
- Cosubstrate (e.g., NAD⁺) dissociates from enzyme in altered form. Prosthetic group (e.g., FAD) stays bound and is regenerated.
- TPP is the coenzyme for ALL alpha-keto acid dehydrogenases - deficit causes pyruvate/lactate buildup (Wernicke encephalopathy).
- PLP is the coenzyme for ALL transamination reactions. Isoniazid blocks PLP - always co-prescribe B6.
- Biotin is covalently attached and is the CO₂ carrier for all carboxylases. Inhibited by avidin (raw eggs).
- NAD⁺ = catabolism; NADPH = anabolism + antioxidant (critical in G6PD deficiency).
- FAD is tightly bound (prosthetic group); yields less ATP per pair of electrons than NADH (1.5 vs 2.5 ATP).
- Ligases use ATP to form bonds (they "ligate" molecules). Hydrolases use water to cleave bonds (no energy required).
Sources: Lippincott Illustrated Reviews: Biochemistry 8e, p.172; Basic Medical Biochemistry: A Clinical Approach 6e, p.241-246; Harper's Illustrated Biochemistry 32e, p.147-152
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