Biochemistry and metabolism — glycolysis, TCA, ETC, fuel switching
**Glycolysis (cytosol):** 1 glucose → 2 pyruvate + 2 ATP (net) + 2 NADH. Rate-limiting step: PFK-1 (inhibited by ATP/citrate, activated by F2,6BP/AMP). Hexokinase I-III (tissue) vs. IV (liver glucokinase, high Km).
**TCA cycle (mitochondrial matrix):** acetyl-CoA → 2 CO₂, 3 NADH, 1 FADH₂, 1 GTP per turn. Rate-limiting: isocitrate dehydrogenase.
**Electron transport chain / oxidative phosphorylation:** • Complex I (NADH dehydrogenase) — rotenone block. • Complex II (succinate dehydrogenase). • Complex III (cytochrome bc1) — antimycin A. • Complex IV (cytochrome oxidase) — CN⁻/CO poisoning. • Complex V (ATP synthase) — oligomycin. Uncouplers (2,4-DNP, aspirin OD, thermogenin in brown fat) dissipate proton gradient as heat.
**Fuel switching:** • Fed state: insulin ↑ → glycolysis, glycogenesis, lipogenesis. • Fasting: glucagon ↑ → glycogenolysis (exhausted by ~18 hrs), gluconeogenesis, ketogenesis. • Prolonged fast / starvation: ketones (β-hydroxybutyrate, acetoacetate) become the brain's primary fuel.
**Key vitamin cofactors:** • B1 thiamine — PDH, α-KG dehydrogenase, transketolase (deficiency: Wernicke-Korsakoff, beriberi). • B2 riboflavin — FAD. B3 niacin — NAD (pellagra: 3 Ds). B5 pantothenate — CoA. B6 pyridoxine — aminotransferases. • B7 biotin — carboxylases. B9 folate — 1-C transfers (neural tube defects). B12 cobalamin — methylmalonyl-CoA mutase, methionine synthase (megaloblastic anemia + neuro).
**Inborn errors** (classic Step 1): PKU (phe → tyr block), MSUD (BCKA-DH), galactosemia (GALT), G6PD deficiency (hemolysis with oxidative stress — fava beans, primaquine, sulfa).