Urea cycle

Question 1

Steps of urea cycle

Answer 1

Mitochondria:
1) Co2 + NH4 = carbamoyl phosphate. Enzyme: CBS1, N-acetylglutamate is allosteric activator

Cytosol
2) Carbamoyl phosphate + ornithine = citrulline. Enzyme: OTC

3) Citrulline + aspartate = arginosuccinate. Enzyme: arginosuccinate synthase
4) Argininosuccinate = arginine Enzyme: argininosuccinase
5) Arginine = ornithine + urea. Enzyme: arginase

Question 2

Nitrogen disposal by muscle (Cori cycle)

Answer 2

1) NH3 from muscle amino acid + alpha-ketoglutarate = glutamate
2) glutamate transfers nitrogen to pyruvate to form alanine, regenerating alpha-ketoglutarate
3) Alanine travels from muscle to liver
4) Alanine passes nitrogen to alpha-ketoglutarate in liver, regenerating pyruvate and forming glutamate
5) Glutamate hands nitrogen off to urea cycle

Question 3

Effect of elevated NH4+ on metabolism

Answer 3

Elevated NH4+ depletes alpha-ketoglutarate, inhibiting the TCA cycle

Question 4

N-acetylglutamate synthase deficiency

Answer 4

NAG required for carbamoyl phosphate synthase I to function. Presents with poor respiration and body temp regulation, poor feeding, developmental delay, intellectual disability in neonate

Question 5

Ornithine transcarbamoylase deficiency

Answer 5

X-linked recessive. Presents in first few days of life. Increased orotic acid as excess carbamoyl phosphate converted to orotic acid

Question 6

Phenylketonuria

Answer 6

Defect: Deficient phenylalanine hydroxylase or cofactor BH4 which converts phenylalanine to tyrosine

Clinical features:

• severe intellectual disability and seizures: elevated phenylalanine and its metabolites cause brain damage
• abnornal pallor of catecholaminergic brain nuclei
• hypopigmentation: elevated phenylalanine suppresses melanin

Inheritance: AR

Treatment: low phenylalanine diet with tyrosine supplementation. Avoid aspartame which contains phe

Question 7

Maple syrup urine disease

Answer 7

Defect: Decreased alpha-ketoacid dehydrogenase. Defect in degrading branched chain amino acids - isoleucine, leucine, valine. Alpha-ketoacids build up in blood

Inheritance: AR

Clinical reagures: CNS defects, intellectual disability, death

Treatment: restrict branched chain amino acids; thiamine supplementation

Question 8

Alkaptonuria

Answer 8

Defect: deficient homogentisate oxidase in tyrosine degradation pathway; leads to pigment forming homogentisic acid accumulation in tissue

Inheritance: AR

Clinical features: dark connective tissue, brown sclerae, urine turns black, arthralgias

Question 9

Homocysteinuria: enzyme defect

Answer 9

Cystathione synthase deficiency or decreased affinity for pyridoxal phosphate

Question 10

Cystinuria

Answer 10

Defect: defect in amino acid transporter in intestine and renal PCT that prevents reabsorption of cystein, ornithine, lysine, arginine

Findings: excess cystine can form stones in urine

Treatment: urinary alkalization, chelating agents