Amino Acid Metabolism

Amino Acid Metabolism

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Amino acid metabolism covers how the body handles the 20 standard amino acids — their synthesis, degradation, and disposal of the amino nitrogen as urea. The nitrogen enters the urea cycle almost exclusively as glutamate and glutamine, funneled into the carbamoyl phosphate synthetase I (CPS-I) step inside hepatic mitochondria.

The single must-know reactions: (1) Transamination by AST/ALT using pyridoxal phosphate (PLP) shuttles α-amino groups to α-ketoglutarate, forming glutamate; (2) Oxidative deamination by glutamate dehydrogenase releases free NH₃ from glutamate and is allosterically activated by ADP, inhibited by GTP; (3) CPS-I commits two mitochondrial ATP toward carbamoyl phosphate, the rate-limiting step, allosterically switched on by N-acetylglutamate (NAG); (4) the urea cycle net equation: 2 NH₃ + CO₂ + 3 ATP → urea + fumarate + 2 ADP + AMP + 4 Pᵢ.

Quick classification: Purely ketogenic amino acids are Leu and Lys (acetyl-CoA/acetoacetate); everything else is glucogenic, with Ile, Phe, Trp, Tyr, Thr also yielding ketone bodies. INI CET loves NAG-as-CPS-I-activator traps and the 3 ATP/4 high-energy phosphate cost of urea synthesis.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Transamination and PLP

Transamination is a reversible amino-group transfer between an amino acid and an α-keto acid, catalysed by aminotransferases (AST = SGOT, ALT = SGPT) using pyridoxal phosphate (PLP) as cofactor. PLP forms a Schiff-base (internal aldimine) intermediate that stabilises a quinonoid carbanion, allowing the α-amino group to be transferred to α-ketoglutarate, generating glutamate. Because the reaction is freely reversible, it doubles as the final step in the biosynthesis of non-essential amino acids from TCA intermediates (e.g., aspartate from oxaloacetate, alanine from pyruvate).

Oxidative Deamination and Transdeamination

Glutamate dehydrogenase (GDH) sits in the mitochondrial matrix and oxidatively removes the amino group of glutamate, releasing free NH₃ and reducing NAD(P)⁺ → NAD(P)H, yielding α-ketoglutarate. ADP activates GDH (low-energy signal, “burn protein for energy”); GTP inhibits it. Coupling transamination (collects amino groups into glutamate) with GDH (releases them as NH₃) is called transdeamination and is the dominant route for nitrogen mobilisation.

The Urea Cycle (Krebs–Henseleit)

Step	Enzyme	Location	Key point
1	CPS-I	Mito matrix	Rate-limiting, requires NAG, uses 2 ATP, NH₃ + CO₂ → carbamoyl phosphate
2	Ornithine transcarbamoylase (OTC)	Mito matrix	Carbamoyl phosphate + ornithine → citrulline
3	Argininosuccinate synthetase	Cytosol	Citrulline + aspartate + ATP → argininosuccinate (consumes the second N)
4	Argininosuccinate lyase	Cytosol	Argininosuccinate → arginine + fumarate
5	Arginase	Cytosol	Arginine → urea + ornithine

Net cost: 3 ATP consumed but 4 high-energy phosphate bonds hydrolysed (2 ATP → 2 ADP at CPS-I, ATP → AMP + PPᵢ at ASS). Fumarate links the cycle to the TCA cycle (anaplerotic) and to gluconeogenesis. NAG is synthesised from glutamate + acetyl-CoA by N-acetylglutamate synthase and is the obligatory allosteric activator of CPS-I — without it, carbamoyl phosphate synthesis is essentially zero.

Nitrogen Transport

Peripheral tissues package amino nitrogen into glutamine (via glutamine synthetase, ATP-dependent) and alanine (glucose–alanine cycle). Liver mitochondrial glutaminase hydrolyses glutamine back to glutamate + NH₃ for CPS-I; kidney uses glutamine amide nitrogen for NH₄⁺ excretion during acidosis.

Classification by Catabolic Fate

• Purely ketogenic: Leu, Lys → acetyl-CoA / acetoacetyl-CoA.
• Glucogenic: Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser, Val.
• Both glucogenic + ketogenic: Ile, Phe, Trp, Tyr, Thr.

Specialised Products (high-yield for INI CET)

• Glycine → heme, purines, glutathione, creatine (with arginine).
• Tyrosine → dopamine → norepinephrine → epinephrine; melanin; thyroid hormones (T3/T4).
• Tryptophan → serotonin → melatonin; NAD⁺/NADP⁺ biosynthesis.
• Arginine → nitric oxide (NO) via NO synthase; creatine; urea.
• Cysteine → taurine (bile-salt conjugation), glutathione.

One-Carbon Metabolism and SAM

S-adenosylmethionine (SAM) is the universal methyl donor, formed from methionine + ATP. After donating its methyl group, SAM becomes S-adenosylhomocysteine → homocysteine. Homocysteine is remethylated to methionine by methionine synthase, using N⁵-methyl-THF and vitamin B₁₂ (methylcobalamin). The folate trap explains why B₁₂ deficiency mimics folate deficiency at the methyl-THF level. Homocysteine can alternatively be condensed with serine by cystathionine β-synthase (B₆-dependent) to form cystathionine — deficiency causes homocystinuria.

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Edge Cases and Regulation

• GDH and hyperinsulinism/hyperammonemia (HI/HA) syndrome: activating mutations in GLUD1 make GDH insensitive to GTP inhibition, causing excessive NH₃ release and recurrent hypoglycaemia — leucine provokes episodes because it allosterically activates the same mutant GDH.
• NAG deficiency vs CPS-I deficiency: both present as neonatal hyperammonemia with low plasma citrulline, but only CPS-I deficiency is unresponsive to NAG/carglumic acid; OTC deficiency shows elevated orotic acid (because carbamoyl phosphate spills into pyrimidine synthesis in the cytosol).
• Fumarate from the urea cycle can refuel the TCA cycle, which is why hyperammonemic states also perturb energy metabolism and explain the cerebral edema of acute ammonia toxicity (glutamate → glutamine accumulation in astrocytes raises osmotic load).

Inborn Errors — Classic INI CET Vignettes

Disorder	Defect	Accumulating substrate
Phenylketonuria (PKU)	Phenylalanine hydroxylase (or BH₄ cofactor)	Phenylalanine, phenylpyruvate; musty odour
Maple syrup urine disease	Branched-chain α-ketoacid dehydrogenase (E1, BCKD)	Leu, Ile, Val; burnt-sugar urine
Alkaptonuria	Homogentisate oxidase	Homogentisic acid; dark urine, ochronosis
Homocystinuria	Cystathionine β-synthase (most common)	Homocysteine; lens dislocation, Marfanoid habitus
Cystinuria	Dibasic amino acid transporter (SLC3A1/SLC7A9)	Cystine stones
Non-ketotic hyperglycinemia	Glycine cleavage system	Glycine in CSF

Connections to Adjacent Topics

• TCA cycle: α-ketoglutarate, oxaloacetate, pyruvate, succinyl-CoA, fumarate and acetyl-CoA are the catabolic entry points — linking this topic to gluconeogenesis, ketogenesis, and anaplerosis.
• Nucleotide metabolism: glycine + aspartate + glutamine donate atoms to the purine ring; aspartate + carbamoyl phosphate (CPS-II, cytosolic, no NAG) form pyrimidines.
• Porphyrias: glycine + succinyl-CoA → δ-aminolevulinic acid (ALA) — the first step of heme synthesis; defects cause neurovisceral or cutaneous porphyrias.
• Neurotransmitter synthesis: tryptophan hydroxylase (BH₄ cofactor) and tyrosine hydroxylase (BH₄) tie amino acid metabolism to monoamine neurotransmitter production — relevant when BH₄ is recycled by dihydropteridine reductase.

Common Exam Traps

1. Confusing CPS-I (mitochondrial, urea, NAG-dependent) with CPS-II (cytosolic, pyrimidines, no NAG).
2. Forgetting that GDH uses NAD⁺ or NADP⁺ — it is the only enzyme with that flexibility.
3. Calling argininosuccinate synthetase the rate-limiting step — it is CPS-I.
4. Assuming all urea-cycle defects cause high orotic acid — only OTC deficiency does, because carbamoyl phosphate accumulation is required.
5. Misclassifying threonine as purely glucogenic — it is both glucogenic and ketogenic.

Worked Micro-Example

During prolonged fasting, muscle protein breakdown releases amino acids. Alanine is transaminated to pyruvate (→ glucose, glucose–alanine cycle) and leucine is oxidised to acetoacetyl-CoA + acetyl-CoA (ketone bodies). The liberated NH₃ is packaged as glutamine (muscle) → transported to liver → glutaminase releases NH₃ → CPS-I (NAG-activated) → through the urea cycle producing 1 urea + 1 fumarate. Cost: 3 ATP, equivalent to 4 ~P. Result: nitrogen excreted, carbon skeletons diverted to glucose or ketones.

INI CET Strategy

Biochemistry carries ~3% of INI CET; amino acid metabolism is a recurring 2–3 question cluster, almost always as clinical vignettes (PKU, MSUD, homocystinuria, hyperammonemia) or mechanism MCQs (cofactors PLP/BH₄/B₁₂, NAG, GDH regulation, urea cycle stoichiometry). Memorise the 3 ATP / 4 high-energy bonds net cost, the purely ketogenic pair (Leu, Lys), and the branched-chain enzyme defect — these appear every exam cycle.

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