Amino Acid Biosynthesis

Amino Acid Biosynthesis

Humans can synthesize only non-essential amino acids (11 of the 20) from metabolic intermediates. Essential amino acids (9) must be supplied in the diet; their deficiency causes specific diseases and growth failure.

Essential vs Non-Essential Amino Acids

Mnemonic for EAA (Phe, Val, Thr, Trp, Ile, Met, His, Arg*, Leu, Lys) — "PVT TIM HALL"

*Arg is conditionally essential (needed in growth; adults can synthesize via urea cycle but not in sufficient amounts).

Non-essential: Ala, Asp, Asn, Glu, Gln, Gly, Pro, Ser, Cys*, Tyr*, Sel. (*Conditionally essential — Cys from Met; Tyr from Phe)

Biosynthetic Routes from Metabolic Intermediates

  • From Pyruvate: Alanine (transamination of pyruvate with Glu), Cysteine (from homocysteine + Serine)
  • From Oxaloacetate (OAA): Aspartate, Asparagine
  • From α-Ketoglutarate: Glutamate (GDH: NH₃ + α-KG → Glu), Glutamine (Glutamine Synthetase: Glu + NH₃ + ATP → Gln — key for ammonia detoxification)
  • From 3-Phosphoglycerate (glycolysis): Serine → Glycine (serine hydroxymethyltransferase, B6, THF) → Cysteine
  • From Glutamate: Proline, Arginine (via partial urea cycle)

Important Amino Acid Derivatives

  • Tyrosine (from Phe): Precursor to Catecholamines (DOPA → Dopamine → Norepinephrine → Epinephrine), Thyroid hormone (T3/T4), Melanin (via DOPA)
  • Tryptophan: Precursor to Serotonin (→ Melatonin), Niacin (B3; 60mg Trp = 1mg Niacin)
  • Histidine: Precursor to Histamine (via histidine decarboxylase, B6)
  • Glycine: Precursor to Heme (with Succinyl-CoA), Purine, Creatine, Bile acids
  • Glutamate: Precursor to GABA (Glutamate decarboxylase, B6)
  • Serine: Precursor to Sphingolipids, Phosphatidylserine, Glycine
  • Arginine: Precursor to Nitric Oxide (NO) via NOS; also Creatine, Polyamines

Creatine Synthesis

Step 1: Arginine + Glycine → Guanidinoacetate [in Kidney]. Step 2: Guanidinoacetate + SAM (methyl donor) → Creatine [in Liver]. Creatine → Creatine Phosphate (phosphocreatine) in muscle — immediate energy buffer. Creatinine = non-enzymatic breakdown product of phosphocreatine; excreted by kidney at constant rate → used to assess GFR.

Inborn Errors of Amino Acid Metabolism

  • PKU (Phenylketonuria): Phenylalanine Hydroxylase deficiency → Phe accumulates → converted to Phenylketones (phenylpyruvate, phenylacetate, phenyllactate). → Fair skin, blue eyes, mousy odor, intellectual disability, eczema. Treat: Phe-restricted diet (avoid aspartame!), BH4 supplementation (for BH4-responsive PKU).
  • Tyrosinemia: Fumarylacetoacetate hydrolase deficiency (Type I) → liver failure, renal tubular dysfunction, cabbage-like odor, hepatocellular carcinoma risk.
  • Alkaptonuria: Homogentisate oxidase deficiency → Homogentisic acid accumulates → darkens in urine (ochronosis), arthritis.
  • Albinism: Tyrosinase deficiency → no Melanin → photosensitivity, vision problems.
  • MSUD (Maple Syrup Urine Disease): Branched-chain α-keto acid dehydrogenase deficiency → Leu, Ile, Val accumulate. Maple syrup odor, encephalopathy, death if untreated. Treatment: Diet low in BCAAs.
  • Homocystinuria: CBS (Cystathionine β-Synthase) deficiency → Homocysteine accumulates. Features: Lens dislocation (downward, ectopia lentis), thromboembolism, intellectual disability, Marfanoid habitus. Elevated homocysteine → atherosclerosis risk. Treatment: B6, folate, B12, methionine restriction.