Lecture 3.2b - Protein and amino acid metabolism

Urea Cycle

• Urea is produced from ammonium ions to prevent toxicity
• Urea is soluble and excreted in urine
• The first reaction in the urea cycle involves the conjugation of ammonia and CO2 to generate carbamoyl phosphate
• The cycle consists of four steps:
  • Carbamoyl phosphate combines with ornithine to form citrulline (inside the mitochondria)
  • Citrulline combines with aspartate to generate argininosuccinate (in the cytoplasm, part of the Krebs cycle)
  • Argininosuccinate is cleaved to generate arginine
  • Arginine is converted to urea by the enzyme arginase, producing ornithine

Urea Cycle in Clinical Context

• Gradually reintroducing nutritional intake in malnourished patients is important to prevent re-feeding syndrome
• Re-feeding syndrome causes:
  • No feedback inhibition for enzymes involved in the urea cycle
  • Increased levels of ammonia
  • Inducible enzymes
  • Hyperammonaemia
• Treatment for re-feeding syndrome involves:
  • Re-feeding at 5-10 kcal/kg/day
  • Gradually increasing to full needs within a week

Defects of Amino Acid Metabolism

• Defects include:
  • Phenylketonuria
  • Tyrosinemia
  • Homocystinuria
  • Non-ketotic hyperglycinemia
  • Maple syrup urine disease
• Over 50 inherited diseases are autosomal recessive
• These disorders are rare (1< 250,000)
• Treatment involves restricting amino acid in diet
• If untreated, may lead to intellectual impairments

Phenylketonuria (PKU)

• Caused by decreased activity of phenylalanine hydroxylase (PAH)
• Symptoms include:
  • Progressive developmental delay
  • Small head circumference
  • Behaviour disturbances
  • Seizures
• Autosomal recessive - chromosome 12
• Treatment involves:
  • Foods low in phenylalanine and protein
• Reference range for phenylalanine in serum: 0.05-0.1 mM
• Phenylketones accumulate in tissue, plasma, and urine
• Diagnosis: heel stick on new-born babies within 48 hours of birth
• Lifelong treatment allows most people with PKU to lead healthy lives

Homocystinuria (HCU)

• Caused by defect in cystathionine beta-synthase
• Symptoms include:
  • Flush of the cheeks
  • Tall, thin frame
  • Lens dislocation
  • Vascular disease
  • Osteoporosis
  • Intellectual disability
  • Psychiatric disorders
• Autosomal recessive - chromosome 21
• Treatment involves:
  • Vitamin B6
  • Folic acid
  • Betaine
  • Dietary restrictions
• Diagnosis: heel stick on new-born babies within 48 hours of birth
• Levels: 5-15 uM
• Symptoms similar to Marfan's syndrome
• Elevated plasma homocysteine is associated with cardiovascular disease
• CBS involved in gasotransmitter hydrogen sulphide synthesis