Amino Acid Metabolism
Reactions
- Deamination → (-) NH₄⁺ → Ketoacid
- Decarboxylation → (-) CO₂ → Amines
Toxic Nature of Ammonia
- Causes cerebral edema
- ↓ GABA (inhibitory neurotransmitter)
- So
- Glutamate + NH₄⁺ → Glutamine
Transamination
Amino Acid | Converted To | Enzyme |
Amino acids | Keto acids | • Transaminase • Require Pyridoxal phosphate (active form of Vitamin B6) |
Alanine | Pyruvate | ALT / SGPT ↳ ALT → PT → Pyruvate |
Aspartate | OAA | AST / SGOT ↳ AST → OT → OAA |
- Site: Cytoplasm of all organs
- Reversible reaction
- Ping-pong mechanism (Bi-bi):
- 2 substrate
- 2 product reaction
Exceptions to Transamination
- Proline
- Hydroxyproline
- Lysine
- Threonine
- Pro (Proline, hydroxyproline) doesn’t lyse (Lysine) through transamination (threonine)
Which one of these amino acids does not enter the Krebs cycle by forming Acetyl CoA via pyruvate?
- Glycine
- Tyrosine
- Hydroxyproline
- Alanine
- Tyrosine:
- Tyrosine → fumarate + acetoacetate.
- Tyre acid ozhikkumbho fumes avum
- These products enter the Krebs cycle
- not through pyruvate or Acetyl CoA.
- Does not use the pyruvate pathway.
ANS
Applied Biochemistry
- Gyrate atrophy (retina & choroid)
- Defect in: δ-ornithine aminotransferase
- Enzyme which undergo Non α amino acid Transamination
- Treatment:
- Restrict ornithine & arginine
- Supplement PLP (B₆)
Transport of NH₃
Transport of NH₃
- 1st-line defence in hyperammonaemia
- Cahill cycle
- Alanine = Transport form from skeletal muscles
- NOTE
- Glutamate + NH3 → Glutamine
- Glutamate = Transport form from other parts
- Enzyme: Glutamine synthetase (in mitochondria)
- Glutamate from
- Amino acids
- NH3 from
- Amino sugars
- Pyrimidine
- Purine
- Porphyrins
Oxidative Deamination
- Site: Liver & Kidney
- Organelle: Mitochondria
- Enzyme: Glutamate dehydrogenase (GDH)
- NADP⁺ → NADPH
- Glutamate → NH₃ → Urea cycle
- Remaining: α-KG
- Activator: NAD⁺/ADP
- Inhibitor: ATP
Urea Cycle (Krebs-Henseleit / Ornithine Cycle)
- Converts toxic Ammonia into non-toxic urea.
- Ammonia is released from amino acid oxidation.
- Site: Liver
- Organelle: Cytoplasm + Mitochondria
- Enzyme: CPS-I (Rate limiting)
- Energetics
- CPS-I: 2 ATP
- AS synthetase: 2 ATP
- Total: 4 ATP used
Contributions
- 1st Nitrogen: Ammonia
- 2nd Nitrogen: Aspartate
- Carbon atom: Respiratory CO₂
Reactions in Cytoplasm + Mitochondria (PUBG)
- Pyrimidine synthesis
- Urea cycle
- Blood: Heme synthesis
- Gluconeogenesis
Urea Cycle Disorders
Urea cycle enzyme Defect | Disorder |
CPS I | Hyperammonemia Type I |
OTC | Hyperammonemia Type II |
AS synthetase | Citrullinemia Type I |
Citrin transporter | Citrullinemia Type II |
AS lyase | Argininosuccinic aciduria |
Arginase | Argininemia |
Ornithine transporter | HHH syndrome |
Step in solving Hyperammonemia and Hyperornithinemia
Citrulline Levels High | ㅤ |
↳ Citrullinemia | ㅤ |
↳ Arginosuccinate aciduria | ㅤ |
Citrulline level Low | ㅤ |
↳ Type 1 Hyperammonemia | Enzyme: CPS 1 • XLR • ↑ Ammonia, glutamate, glutamine • Normal Orotic acid & Uracil Symptoms when ↑ Protein intake • Lethargy, Confusion, coma • Vomiting, Hyperventilation |
Citrulline Level Normal + Hyperornithinemia | ㅤ |
↳ HHH Syndrome • Hyperornithinemia →→→→→→→→→ • Hyperammonemia →→→→→→→→→ • Homocitrullinuria →→→→→→→→→→ | Enzyme: Mitochondrial ornithine transporter (ORNT1) • ↑ Ornithine • ↑ Ammonia • ↑ Homocitrulline (d/t CP reacting with lysine). Treatment • Protein restriction • Ammonia-scavenging (sodium benzoate, phenylbutyrate) • Arginine or citrulline supplementation ↳ to improve urea cycle flux |
↳ Gyrate Atrophy of Choroid and Retina | Enzyme: OAT deficiency • AR • OAT deficiency→ ⛔ breakdown of Ornithine • Source: From Arginine • Ornithine is toxic to Retinal Pigment Epithelium (RPE) • Progressive chorioretinal degeneration ↳ night blindness, visual loss Treatment • Low-arginine diet • B6 supplementation Arni (Ornithine) kk avlde Kannu (RPE) kandapo Urge (Arginine) ayi → Glued (GLutamate) ayi |
Citrulline Level Normal + Hyperornithinemia + Orotic Aciduria | ㅤ |
↳ Type 2 Hyperammonemia | Enzyme: OTC • (m/c UCD) • AR • ↑Ammonia, glutamate, glutamine • ↑↑ Orotic acid & Uracil ⇒ Orotic aciduria • Accumulation of ornithine Symptoms • Type 1 + Hepatomegaly |
Just Orotic Aciduria | ㅤ |
Hereditary orotic aciduria | Enzyme: UMP synthase deficiency • AR • ↑ Orotic acid in urine • Megaloblastic anemia unresponsive to B12/folate • Normal ammonia (differentiates from OTC deficiency). Symptoms • Failure to thrive • Growth retardation • Developmental delay Treatment • Uridine supplementation ↳ provides UMP, bypasses block, decreases orotic acid |
Allopurinol | ㅤ |
Screening for IEM
- IOC / Gold standard: Tandem Mass Spectrometry:
- Blood spot
- Gas Chromatography - Mass Spectrometry:
- Fresh Urine
- High Performance Liquid chromatography/Electrophoresis:
- Plasma, urine
- Blood pH
- ↑/Normal: UCD
- ↓: Organic aciduria
- Acylation therapy / AMMONIA SCAVENGERS
- Phenyl butyrate (prodrug)
- Phenyl acetate + Glutamine → Phenyl acetyl glutamine (excreted)
- Mnemonic: But → Glut
- Sodium benzoate + Glycine → Benzoyl glycine/hippurate (excreted)
- (via Glycine synthase)
- Mnemonic: Benz → Glazing
- Glycine requires NH₃ + CO₂ + 1 Carbon group
Key differentiator in exams:
- Hyperornithinemia → think urea cycle defects or retinal disease.
- Orotic aciduria → think megaloblastic anemia + orotic acid in urine + normal ammonia.
- OTC deficiency: Hyperammonemia, no anemia.
Argininemia
- Least hyperammonemia
- Spastic diplegia + scissoring gait
- Urge to cut with Scissor () to 2 pieces (Diplegia)
Argininosuccinic Aciduria
Trichorrhexis nodosa (brittle hair)
- Enzyme deficient:
- Arginosuccinate lyase
- Also caused by
- Menke’s kinky hair
- Hypothyroidism
- Iron deficiency
- Mnemonic: Manka () was Iron () and thyroid deficent ()
- Urge (Arginosuccinate lyase) to pull hair
General Clinical Features
- Encephalopathy
- Respiratory alkalosis
- Tachypnoea
- Hyperammonemia + ↑ plasma glutamine
Neonates:
- feeding difficulties,
- failure to thrive,
- lethargy,
- convulsions, coma
NOTE: NETHERTON SYNDROME
- Netherland → Bamboo (Bamboo hair), Fish (Icthyosis), Spin (SPINK)
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