Core Topics: Amino Acid Metabolism

How to Use This Resource

Each pathway section includes: Core Concepts (location, net reaction), Key Enzymes (regulatory steps), and High-Yield Facts (clinical correlations, deficiencies). Use for active recall, spaced repetition, and integration with clinical cases.

Amino Acid Catabolism

Transamination, deamination, and carbon skeleton fate determination

Transamination Reactions

Function: Transfer of amino groups to α-ketoglutarate → glutamate
Cofactor: Pyridoxal phosphate (vitamin B6) required for all aminotransferases
ALT (Alanine Aminotransferase): Alanine + α-KG ↔ Pyruvate + Glutamate (liver-specific)
AST (Aspartate Aminotransferase): Aspartate + α-KG ↔ Oxaloacetate + Glutamate (heart, liver, muscle)
Clinical: Elevated ALT/AST indicates hepatocellular injury

Oxidative Deamination

Location: Mitochondria (primarily liver)
Enzyme: Glutamate Dehydrogenase
Reaction: Glutamate + NAD(P)⁺ → α-Ketoglutarate + NH₄⁺ + NAD(P)H
Function: Produces free ammonia (NH₄⁺) for urea cycle
Regulation: Activated by ADP; inhibited by ATP, GTP, NADH

Carbon Skeleton Fates

Type	Fate	Amino Acids
Glucogenic	→ Glucose (via gluconeogenesis)	Most amino acids
Ketogenic	→ Ketone bodies (acetoacetate)	Leucine, Lysine (only purely ketogenic)
Both	→ Glucose + Ketones	Isoleucine, Phenylalanine, Tryptophan, Tyrosine, Threonine

Mnemonic: "PITTT" for Both (Phe, Ile, Trp, Thr, Tyr)

High-Yield: Amino Acid Catabolism

Vitamin B6 Dependency

Pyridoxal phosphate (B6) required for ALL transamination reactions; deficiency → impaired amino acid metabolism

BCAA Metabolism

Branched-chain amino acids (Leu, Ile, Val) degraded in muscle (not liver); requires branched-chain α-ketoacid dehydrogenase

Essential Amino Acids

"PVT TIM HALL": Phe, Val, Thr, Trp, Ile, Met, His, Arg (conditional), Leu, Lys

Clinical Correlation

Maple syrup urine disease = branched-chain α-ketoacid dehydrogenase deficiency → ↑Leu, Ile, Val; sweet-smelling urine

Urea Cycle

Hepatic conversion of toxic ammonia to urea for renal excretion

Location & Function

Location: Mitochondria (first 2 steps) + Cytoplasm (last 3 steps)
Function: Convert toxic NH₄⁺ (from amino acid catabolism) → urea (water-soluble, excreted by kidneys)
Energy Cost: 4 high-energy phosphate bonds per urea molecule
Nitrogen Sources: 1 from NH₄⁺, 1 from aspartate
Clinical: Urea cycle disorders → hyperammonemia → neurologic damage (asterixis, cerebral edema)

5 Main Enzymes

Carbamoyl Phosphate Synthetase I (CPS-I)

NH₄⁺ + CO₂ + 2 ATP → Carbamoyl phosphate (rate-limiting, mitochondria); requires N-acetylglutamate

Ornithine Transcarbamylase (OTC)

Carbamoyl phosphate + Ornithine → Citrulline (mitochondria)

Argininosuccinate Synthetase

Citrulline + Aspartate + ATP → Argininosuccinate (cytoplasm)

Argininosuccinate Lyase

Argininosuccinate → Arginine + Fumarate (cytoplasm)

Arginase

Arginine → Ornithine + Urea (cytoplasm)

Disorders & Treatment

OTC Deficiency: Most common; X-linked; ↑orotic acid (carbamoyl phosphate shunted to pyrimidine synthesis)
Other Deficiencies: Autosomal recessive (CPS-I, argininosuccinate synthetase/lyase, arginase)
Presentation: Hyperammonemia (vomiting, lethargy, seizures, cerebral edema), respiratory alkalosis
Treatment: Low-protein diet, ammonia scavengers (sodium benzoate, sodium phenylacetate), arginine supplementation, dialysis (acute)
N-Acetylglutamate: Essential activator of CPS-I; deficiency mimics CPS-I deficiency

High-Yield: Urea Cycle

Rate-Limiting Step

CPS-I is rate-limiting; activated by N-acetylglutamate (synthesized from acetyl-CoA + glutamate)

OTC Deficiency

X-linked (males severely affected); ↑orotic acid distinguishes from CPS-I deficiency (no orotic acid elevation)

Ammonia Detoxification

Alanine (muscle→liver via glucose-alanine cycle) and Glutamine (all tissues→liver/kidney) transport ammonia safely

Hyperammonemia Treatment

Sodium benzoate/phenylacetate bind amino acids → excreted as hippurate/phenylacetylglutamine (nitrogen waste removal)

Heme Synthesis

Mitochondrial and cytoplasmic synthesis of heme for hemoglobin and cytochromes

Location & Regulation

Location: Mitochondria (first + last steps) + Cytoplasm (intermediate steps)
Tissues: Bone marrow (erythroid cells), liver (hepatocytes)
Rate-Limiting Enzyme: δ-Aminolevulinic Acid (ALA) Synthase
Reaction: Glycine + Succinyl-CoA → ALA (requires pyridoxal phosphate/B6)
Regulation: Inhibited by heme (feedback), glucose; induced by cytochrome P450 inducers (phenytoin, griseofulvin, sulfonamides)

Key Synthesis Steps

ALA Synthase

Glycine + Succinyl-CoA → ALA (mitochondria; rate-limiting)

ALA Dehydratase

2 ALA → Porphobilinogen (cytoplasm); inhibited by lead

Porphobilinogen Deaminase

Porphobilinogen → Hydroxymethylbilane; deficient in AIP

Ferrochelatase

Protoporphyrin IX + Fe²⁺ → Heme (mitochondria); inhibited by lead

Porphyrias & Lead Poisoning

Acute Intermittent Porphyria (AIP): Porphobilinogen deaminase deficiency; 5 P's: Pain (abdominal), Port-wine urine, Polyneuropathy, Psychological disturbances, Precipitated by drugs/alcohol/fasting
Porphyria Cutanea Tarda (PCT): Uroporphyrinogen decarboxylase deficiency; most common; photosensitivity, blistering skin, tea-colored urine
Lead Poisoning: Inhibits ALA dehydratase + ferrochelatase; ↑ALA, ↑protoporphyrin, basophilic stippling, microcytic anemia, neurologic symptoms (children), abdominal pain
Treatment: AIP (glucose, heme arginate); PCT (phlebotomy, chloroquine); Lead (succimer, EDTA, dimercaprol)

High-Yield: Heme Synthesis

Rate-Limiting Enzyme

ALA synthase requires vitamin B6; induced by P450 inducers → acute porphyria attacks

AIP Mnemonic

5 P's: Pain (abdominal), Port-wine urine, Polyneuropathy, Psychological, Precipitated by drugs

Lead Poisoning

Inhibits 2 enzymes (ALA dehydratase, ferrochelatase) → ↑ALA + ↑protoporphyrin; basophilic stippling on smear

PCT Features

Most common porphyria; photosensitivity with blistering; associated with hepatitis C, alcohol, estrogen

Heme Degradation

Breakdown of heme to bilirubin and excretion via bile/intestine

Degradation Pathway

Heme Oxygenase

Heme → Biliverdin (green pigment) + CO + Fe²⁺ (recycled)

Biliverdin Reductase

Biliverdin → Unconjugated Bilirubin (indirect, water-insoluble)

Albumin Transport

Unconjugated bilirubin bound to albumin → liver

UGT1A1

Unconjugated → Conjugated bilirubin (direct, water-soluble) in liver

Intestinal Bacteria

Conjugated bilirubin → Urobilinogen → Stercobilin (feces, brown) + Urobilin (urine, yellow)

Hyperbilirubinemia Types

Type	Cause	Examples
Unconjugated	↑Production or ↓conjugation	Hemolysis, Gilbert syndrome, Crigler-Najjar
Conjugated	↓Excretion or obstruction	Dubin-Johnson, Rotor syndrome, biliary obstruction

Gilbert Syndrome: Mild ↓UGT1A1 activity; asymptomatic jaundice during stress/fasting
Crigler-Najjar: Type I (severe, no UGT1A1 → kernicterus); Type II (moderate, responds to phenobarbital)
Dubin-Johnson: Defective excretion; black liver on gross pathology
Neonatal Jaundice: Physiologic (immature UGT1A1); treated with phototherapy

Kernicterus

Pathophysiology: Unconjugated bilirubin (lipid-soluble) crosses blood-brain barrier → deposits in basal ganglia
Risk Factors: Prematurity, hemolytic disease (Rh/ABO incompatibility), G6PD deficiency, breastfeeding jaundice
Clinical: Lethargy, hypotonia, poor feeding → progression to hypertonia, opisthotonos, hearing loss, cerebral palsy
Prevention: Monitor bilirubin levels, phototherapy, exchange transfusion (severe cases)
Phototherapy: Converts unconjugated bilirubin to water-soluble isomers excreted in bile/urine

High-Yield: Heme Degradation

Conjugation Enzyme

UGT1A1 (UDP-glucuronosyltransferase) conjugates bilirubin in liver; deficient in Gilbert/Crigler-Najjar

Stool/Urine Color

Stercobilin → brown feces; Urobilin → yellow urine; pale stools + dark urine = biliary obstruction

Kernicterus Risk

Only unconjugated bilirubin crosses BBB; sulfonamides displace bilirubin from albumin → ↑kernicterus risk

Dubin-Johnson

Conjugated hyperbilirubinemia; black liver on gross pathology (epinephrine metabolite accumulation)

One-Carbon Metabolism

Folate and B12-dependent transfer of one-carbon units for biosynthesis

Key Carriers & Donors

Tetrahydrofolate (THF): Primary one-carbon carrier; accepts/donates methyl, methylene, formyl groups
S-Adenosylmethionine (SAM): Universal methyl donor for methylation reactions (DNA, proteins, neurotransmitters)
Vitamin B12 (Cobalamin): Required for methyl-THF → THF conversion; deficiency traps folate as methyl-THF
Vitamin B6: Required for homocysteine → cysteine conversion (cystathionine β-synthase)

Homocysteine Metabolism

Remethylation Pathway

Homocysteine + Methyl-THF → Methionine (requires B12); Methionine → SAM → SAH → Homocysteine

Transsulfuration Pathway

Homocysteine + Serine → Cystathionine → Cysteine (requires B6; cystathionine β-synthase)

Biosynthetic Uses

Purine Synthesis: Formyl-THF provides carbons 2 and 8 of purine ring
Thymidylate Synthesis: Methylene-THF converts dUMP → dTMP (thymidylate synthase); critical for DNA synthesis
Methionine Synthesis: Methyl-THF donates methyl group to homocysteine (B12-dependent)
Clinical: Folate/B12 deficiency → impaired DNA synthesis → megaloblastic anemia

High-Yield: One-Carbon Metabolism

Folate Trap

B12 deficiency traps folate as methyl-THF (cannot convert back to THF) → functional folate deficiency

Megaloblastic Anemia

Both folate and B12 deficiency cause megaloblastic anemia; only B12 deficiency causes neurologic symptoms (subacute combined degeneration)

Homocystinuria

Cystathionine β-synthase deficiency → ↑homocysteine; lens dislocation (downward), intellectual disability, thrombosis, tall stature

Neural Tube Defects

Folate deficiency in pregnancy → neural tube defects (spina bifida, anencephaly); supplement before conception

Protein Folding & Quality Control

Cellular mechanisms for proper protein folding and degradation of misfolded proteins

Protein Structure Levels

Primary: Amino acid sequence (peptide bonds)
Secondary: Local folding patterns (α-helix, β-sheet; hydrogen bonds)
Tertiary: 3D folding (disulfide bonds, hydrophobic interactions, ionic bonds, hydrogen bonds)
Quaternary: Multiple polypeptide subunits (hemoglobin, immunoglobulins)
Denaturation: Loss of secondary/tertiary structure (heat, pH, chemicals); primary structure intact

Chaperones & Folding

Heat Shock Proteins (HSP70, HSP60)

Prevent aggregation, assist refolding of denatured proteins; upregulated during stress

Protein Disulfide Isomerase (PDI)

Forms/breaks disulfide bonds in ER; ensures correct cysteine pairing

Peptidyl Prolyl Isomerase

Catalyzes cis-trans isomerization of proline peptide bonds

Degradation Systems

Ubiquitin-Proteasome System: Ubiquitin tags misfolded proteins → 26S proteasome degrades (ATP-dependent)
Unfolded Protein Response (UPR): ER stress response; ↑chaperone production, ↓protein synthesis, ↑ERAD (ER-associated degradation)
Lysosomal Degradation: Autophagy of organelles/protein aggregates (especially in long-lived cells)
Protein Misfolding Diseases: Alzheimer's (amyloid-β, tau), Parkinson's (α-synuclein/Lewy bodies), Prion diseases (PrP^Sc), Cystic fibrosis (ΔF508 CFTR)

High-Yield: Protein Folding

Chaperone Function

HSP70/HSP60 prevent aggregation during folding; require ATP; upregulated in heat shock/stress

Ubiquitination

E1 (activating) → E2 (conjugating) → E3 (ligase; substrate-specific) → polyubiquitin chain → proteasome recognition

Prion Diseases

PrP^C → PrP^Sc conformational change (α-helix → β-sheet); infectious, neurodegenerative (CJD, kuru, mad cow)

Cystic Fibrosis

ΔF508 mutation → CFTR misfolding → ER retention/degradation → no chloride channel at cell surface

Amino Acid Disorders (Inborn Errors)

Genetic defects in amino acid metabolism with characteristic clinical presentations

Phenylketonuria (PKU)

Defect: Phenylalanine hydroxylase deficiency (or BH₄ cofactor)
Findings: ↑Phenylalanine, ↓Tyrosine; intellectual disability, musty/mousy odor, fair skin, eczema, seizures
Treatment: Low-phenylalanine diet, tetrahydrobiopterin (BH₄) supplementation in some cases
Screening: Newborn screening (Guthrie test)

Homocystinuria

Defect: Cystathionine β-synthase deficiency (most common)
Findings: ↑Homocysteine, ↑Methionine; lens dislocation (downward/inward), intellectual disability, thrombosis, tall stature, marfanoid habitus
Treatment: Vitamin B6 (pyridoxine) responsive in some, low-methionine diet, betaine, B12/folate supplementation

Maple Syrup Urine Disease

Defect: Branched-chain α-ketoacid dehydrogenase deficiency
Findings: ↑Leucine, Isoleucine, Valine; sweet/burnt sugar-smelling urine, poor feeding, vomiting, neurologic decline, ketoacidosis
Treatment: Restrict BCAAs, thiamine (B1) supplementation (cofactor), liver transplant (severe)

Alkaptonuria

Defect: Homogentisate oxidase deficiency
Findings: Dark urine on standing (oxidation of homogentisic acid), ochronosis (blue-black connective tissue), early-onset arthritis
Treatment: Low-protein diet, vitamin C (may slow progression), joint replacement

Albinism

Defect: Tyrosinase deficiency (most common type)
Findings: Lack of melanin; pale skin/hair, blue eyes, vision problems (nystagmus, photophobia), ↑skin cancer risk
Treatment: Sun protection, vision correction, regular skin cancer screening

Cystinuria

Defect: Defective cystine transporter (COLA: Cystine, Ornithine, Lysine, Arginine)
Findings: Cystine kidney stones (hexagonal crystals), recurrent nephrolithiasis, flank pain
Treatment: Hydration, alkalinize urine (potassium citrate), chelators (penicillamine, tiopronin)

Hartnup Disease

Defect: Defective neutral amino acid transporter (tryptophan)
Findings: Pellagra-like symptoms (niacin deficiency): dermatitis, diarrhea, dementia; cerebellar ataxia
Treatment: Niacin (vitamin B3) supplementation, high-protein diet

Tyrosinemias

Type I: Fumarylacetoacetate hydrolase deficiency; liver failure, renal tubular dysfunction, ↑AFP, hepatocellular carcinoma risk
Type II: Tyrosine aminotransferase deficiency; eye/skin lesions, intellectual disability
Treatment: Nitisinone (Type I), low-tyrosine/phenylalanine diet

High-Yield: Amino Acid Disorders

PKU Screening

Newborn screening mandatory; maternal PKU → fetal microcephaly, intellectual disability, congenital heart defects (teratogenic effect of ↑Phe)

Homocystinuria vs Marfan

Both tall/maranoid; Homocystinuria: lens dislocation downward, intellectual disability, thrombosis; Marfan: lens upward, no ID, aortic root dilation

MSUD Treatment

Thiamine (B1) is cofactor for branched-chain α-ketoacid dehydrogenase; some patients respond to high-dose B1

Cystine Stones

Hexagonal crystals pathognomonic; acidic urine promotes stone formation → alkalinize urine to increase solubility

Back to Library Next: Nucleotide Metabolism

Evidence & Further Reading

Berg JM et al. Biochemistry. 9th ed. W.H. Freeman; 2019.
Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. W.H. Freeman; 2021.
USMLE Content Outline 2025. Federation of State Medical Boards & NBME.
Scriver CR et al. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill; 2001.
Mudd SH et al. Homocystinuria: clinical and biochemical spectrum. J Inherit Metab Dis. 2020;43(1):31-44.
Bonkovsky HL et al. Porphyrias: diagnosis and management. Hepatology. 2019;70(4):1428-1444.