Biochemistry — Metabolic Maps — USMLE Step 1 Notes
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Enzyme-deficiency diseases the exam returns to
- Von Gierke (I): glucose-6-phosphatase → severe fasting hypoglycaemia, lactic acidosis, hepatomegaly
- Pompe (II): lysosomal acid alpha-glucosidase → cardiomegaly, hypotonia
- McArdle (V): myophosphorylase → exercise intolerance, no lactate rise on exertion
- Classic galactosemia: GALT → cataracts, jaundice, hepatomegaly with lactose feeding
- PKU: phenylalanine hydroxylase → musty odour, intellectual disability; restrict phenylalanine
Urea cycle
- OTC deficiency: X-linked, high ammonia, high orotic acid, low BUN
- Orotic acid HIGH + ammonia HIGH → OTC; orotic acid high + ammonia NORMAL → hereditary orotic aciduria
Vitamins as cofactors
- B1 (thiamine): pyruvate dehydrogenase, transketolase → Wernicke; give before glucose
- B6 (pyridoxine): transaminases, neurotransmitters → depleted by isoniazid
- B12 and folate: methylation and DNA synthesis → megaloblastic anaemia
- B12 uniquely also causes subacute combined degeneration; folate does not
Central metabolism — where and rate-limiting steps
| Pathway | Rate-limiting enzyme | Note |
|---|---|---|
| Glycolysis | PFK-1 | Cytoplasm; nets 2 ATP + 2 NADH |
| Gluconeogenesis | Fructose-1,6-bisphosphatase | Liver/kidney; needs pyruvate carboxylase (biotin) |
| TCA cycle | Isocitrate dehydrogenase | Mitochondria; 3 NADH, 1 FADH2, 1 GTP per turn |
| Glycogen synthesis | Glycogen synthase | Insulin-activated |
| Fatty acid synthesis | Acetyl-CoA carboxylase | Cytoplasm; needs citrate + NADPH |
| Cholesterol synthesis | HMG-CoA reductase | Statin target |
| Urea cycle | Carbamoyl phosphate synthetase I | Ammonia disposal |
Electron transport & energy
- NADH and FADH2 feed the electron transport chain; the proton gradient drives ATP synthase. Uncouplers (2,4-DNP, thermogenin) dissipate the gradient as heat.
- Cyanide and CO block complex IV; rotenone complex I; oligomycin ATP synthase.
Amino-acid & storage disorders
- PKU — phenylalanine hydroxylase deficiency; musty odour, intellectual disability; restrict phenylalanine, avoid aspartame.
- Maple syrup urine disease — branched-chain ketoacid dehydrogenase; sweet urine.
- Homocystinuria — lens dislocates DOWN, thrombosis; vs Marfan (up).
- Von Gierke (I) — G6Pase; severe fasting hypoglycaemia, hepatomegaly. Pompe (II) — lysosomal; cardiomegaly. McArdle (V) — muscle phosphorylase; exercise intolerance, no lactate rise.
Vitamins — deficiency at a glance
- B1 thiamine → Wernicke-Korsakoff, beriberi; B3 niacin → pellagra (3 D's); B6 → sideroblastic anaemia, isoniazid; B9/B12 → megaloblastic anaemia (B12 also neuro/methylmalonic acid).
- C → scurvy (collagen, bleeding gums); D → rickets/osteomalacia; A → night blindness; E → haemolysis/ataxia; K → bleeding (clotting factors).
Molecular biology essentials
- Replication: helicase unwinds, primase lays RNA primer, DNA pol III synthesises (3'→5' proofreading), pol I replaces primer, ligase seals.
- Repair: nucleotide-excision (xeroderma pigmentosum), mismatch (Lynch), base-excision (deamination), non-homologous end-joining (ataxia-telangiectasia).
- Transcription → mRNA (RNA pol II); translation on ribosomes; start = methionine (AUG).
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