Amino Acid Metabolism

Amino Acid Metabolism

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Amino acid metabolism is the set of pathways that handle dietary and endogenous amino acids: removal of the α-amino group via transamination (catalysed by aminotransferases using pyridoxal phosphate / PLP) and oxidative deamination (catalysed by glutamate dehydrogenase, GDH), followed by disposal of ammonia through the urea cycle (Krebs–Henseleit). The carbon skeletons are funnelled into the TCA cycle and classified as glucogenic (most), ketogenic (Leu, Lys), or mixed (Ile, Phe, Trp, Tyr, Thr). Essential amino acids (Val, Leu, Ile, Thr, Met, Phe, Trp, Lys, His, Arg-conditionally) cannot be synthesised de novo. FMGE high-yield: AST (SGOT) rises in myocardial injury, ALT (SGGT) is more liver-specific; inborn errors — PKU (phenylalanine hydroxylase, restrict Phe, avoid aspartame), MSUD (branched-chain α-ketoacid dehydrogenase, sweet-smelling urine), homocystinuria (cystathionine β-synthase), alcaptonuria (homogentisate oxidase, dark urine, ochronosis). One-carbon units flow via THF, SAM (universal methyl donor), and methylcobalamin.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Nitrogen Removal — Two Coupled Reactions

Transamination reversibly shifts the α-amino group from any amino acid to α-ketoglutarate, forming glutamate and a new α-keto acid. Two clinically vital aminotransferases are ALT (alanine aminotransferase, cytosolic, abundant in liver) and AST (aspartate aminotransferase, mitochondrial + cytosolic, abundant in heart, liver, skeletal muscle, kidney). Both require PLP as the amino-group carrier. The reactions:

• ALT: Alanine + α-ketoglutarate ⇌ Pyruvate + Glutamate
• AST: Aspartate + α-ketoglutarate ⇌ Oxaloacetate + Glutamate

Oxidative deamination of glutamate by glutamate dehydrogenase (liver mitochondria, uses NAD⁺ or NADP⁺) liberates free NH₄⁺, which enters the urea cycle. GDH is allosterically activated by ADP/GTP-loss signalling low energy and inhibited by GTP — coupling amino acid catabolism to the energy state.

The Urea Cycle (Krebs–Henseleit)

Occurs across mitochondrial matrix and cytosol. Two nitrogens are eliminated: one from free NH₄⁺ (via carbamoyl phosphate) and one from aspartate.

Step	Location	Enzyme	N source
1	Mitochondria	CPS-I (rate-limiting, activated by N-acetylglutamate)	NH₄⁺ + CO₂ + 2 ATP → carbamoyl phosphate
2	Mitochondria	Ornithine transcarbamoylase	Carbamoyl phosphate + ornithine → citrulline
3	Cytosol	Argininosuccinate synthetase (uses 2 ATP-equivalent via ATP→AMP+PPi)	Citrulline + aspartate → argininosuccinate
4	Cytosol	Argininosuccinate lyase	→ arginine + fumarate
5	Cytosol	Arginase	Arginine → urea + ornithate (returns to mitochondria)

Net cost: 3 ATP (4 high-energy phosphate bonds). Fumarate links the urea cycle to the TCA cycle. Hyperammonemia in CPS-I or OTC deficiency presents with lethargy, cerebral edema, raised glutamine.

Carbon Skeleton Fate

Glucogenic amino acids catabolise to pyruvate, oxaloacetate, α-ketoglutarate, succinyl-CoA, or fumarate (gluconeogenesis substrates). Purely ketogenic: Leu, Lys. Both: Ile, Phe, Trp, Tyr, Thr.

FMGE Question Patterns

• Match the transaminase with the disease (ALT↑ = viral hepatitis; AST>ALT = alcoholic liver disease).
• Identify the rate-limiting enzyme of the urea cycle (CPS-I).
• Recall which two amino acids are exclusively ketogenic (Leu, Lys) — a frequent one-liner.
• Identify the cofactor of phenylalanine hydroxylase (BH₄ / tetrahydrobiopterin), not PLP.

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Edge Cases & Exam Traps

• GDH uniqueness: It is the only enzyme that uses both NAD⁺ and NADP⁺ and the only amino-acid-catabolising enzyme not requiring PLP. ADP allosterically activates it; GTP inhibits it — this is the molecular basis for increased amino acid oxidation during fasting/starvation (low ATP/GTP).
• N-acetylglutamate (NAG): synthesised from glutamate + acetyl-CoA by N-acetylglutamate synthase; degraded by a hydrolase. Arginine activates NAG synthase, explaining why a high-protein meal (or arginine infusion) boosts CPS-I activity. N-carbamoylglutamate (carglumic acid) is used pharmacologically as a NAG analogue to treat NAGS deficiency.
• Aspartate–argininosuccinate shunt: fumarate released by argininosuccinate lyase can re-enter the TCA cycle, providing a direct carbon link between nitrogen disposal and energy metabolism.
• Hepatic encephalopathy therapy: lactulose acidifies the colon → traps NH₃ as non-absorbable NH₄⁺; rifaximin reduces ammonia-producing gut flora; L-ornithine-L-aspartate (LOLA) supplies urea-cycle intermediates.
• Isoenzymes confusing AST: mitochondrial vs cytosolic AST exist; mitochondrial AST is released late in cell death. The De Ritis ratio (AST/ALT) >2 strongly suggests alcoholic hepatitis; >1 with ALT <300 suggests cirrhosis.
• Transdeamination = transamination followed by oxidative deamination of glutamate; this is the canonical route for catabolising most amino acid nitrogen.
• Glucose–alanine cycle (Cahill): muscle transaminates pyruvate → alanine (ALT), ships it to liver; kidney also takes up glutamine, releasing NH₄⁺ for urinary excretion (especially in chronic acidosis).

One-Carbon Metabolism (linking amino acids to nucleotides and methylation)

THF carries one-carbon units at oxidation states: 5,10-methylene-THF (donates methyl to dUMP → dTMP via thymidylate synthase), 10-formyl-THF (purine C2 and C8). SAM (S-adenosylmethionine) is the universal methyl donor; after donating its methyl it becomes SAH (S-adenosylhomocysteine), then homocysteine, which is either remethylated to methionine by methionine synthase (B12-dependent, MTR) using 5-methyl-THF, or enters the trans-sulphuration pathway via cystathionine β-synthase (PLP-dependent) to form cysteine. Hyperhomocysteinaemia is a risk factor for thrombosis and atherosclerosis; folate + B12 + B6 lower it.

Inborn Errors of Metabolism — Must-Know Triad

• PKU — Phe hydroxylase (or BH₄ synthesis) deficiency; high Phe neurotoxic; treatment: dietary Phe restriction + tyrosine supplementation; aspartame avoidance (contains Phe–Asp dipeptide). Maternal PKU causes fetal microcephaly/heart defects.
• MSUD — branched-chain α-ketoacid dehydrogenase (BCKD) deficiency; accumulation of Leu, Ile, Val and their α-keto acids; burnt-sugar/maple syrup odour; treat with BCAA-restricted diet and thiamine (some patients are thiamine-responsive).
• Homocystinuria — most commonly cystathionine β-synthase deficiency; lens subluxation downward (vs Marfan upward), intellectual disability, thrombosis; responsive to pyridoxine in ~50% cases.

Practice Prompts

1. A 3-month infant has vomiting, lethargy, and plasma ammonia of 900 µmol/L with low citrulline and high orotic acid after a protein-rich meal. Which urea-cycle enzyme is most likely deficient? (OTC deficiency — X-linked; high orotic acid differentiates from CPS-I deficiency.)
2. Why does aspartame worsen PKU, and why must PKU patients be supplemented with tyrosine? (Aspartame releases Phe on hydrolysis; Phe hydroxylase block prevents endogenous Tyr synthesis, making Tyr conditionally essential.)

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