Protein and Amino Acid Metabolism Lecture 3.2b PDF

Urea cycle: ◦Urea is produced from ammonium ions Titanagperabhadrected ◦Precents toxicity of ammonium ◦Soluble, excreted in urine Urea cycle - summary: ◦First reaction (entering the cycle): ‣ Amm...

Urea cycle: ◦Urea is produced from ammonium ions Titanagperabhadrected ◦Precents toxicity of ammonium ◦Soluble, excreted in urine Urea cycle - summary: ◦First reaction (entering the cycle): ‣ Ammonia and CO2 conjugates to generate carbamoyl phosphate ◦Urea cycle: ‣ Step 1: Carbamoyl phosphate combines with ornithine to form citrulline (inside the mitochondria) ‣ Step 2: In the cytoplasm, citrulline combines with aspartate to generate argininosuccinate - this happens as part of the Krebs cycle, also known as TCA cycle ‣ Step 3: Cleavage of argininosuccinate generates arginine ‣ Step 4: The enzyme arginase catalases the generation of urea from arginine, producing ornithine Urea cycle in the clinical context: ◦Why is it important to gradually reintroduce nutritional intake in malnourished patients?: ‣ Re-feeding syndrome: No feedback inhibition for enzymes involved in the urea cycle - increased levels of ammonia Inducible enzymes Hyperammonaemia ◦E.g. cases of hyperammonemic encephalopathy ◦Re-feed @ 5-10 kcal/kg/day. Raise gradually to full needs within a week Defects of amino acid metabolism: ◦Disorders include: phenylketonuria, tyrosinemia, homocystinuria, non-ketotic hyperglycinemia and maple syrup urine disease ◦Over 50 inherited diseases ◦These disorders are autosomal recessive ◦Rare (1< 250,000) ◦Treatment - restriction of amino acid in diet ◦If untreated, may lead to intellectual impairments Phenylketonuria (PKU): ◦Caused by decreased activity of phenylalanine hydroxylase (PAH) ◦Progressive developmental delay, a small head circumference, behaviour disturbances and seizures ◦Autosomal recessive - chromosome 12 ◦Treatment - foods low in phenylalanine and protein ◦Reference range for phenylalanine in serum - 0.05-0.1 mM ◦Phenylketones accumulates in tissue, plasma and urine ◦Diagnosis - heel stick on new-born babies within 48 hours of birth  ◦With lifelong treatment, most people living with PKU lead healthy lives Homocystinuria (HCU): ◦Caused by defect in cystathionine beta-synthase ◦Flush of the cheeks, a tall, thin frame, lens dislocation, vascular disease, osteoporosis. Intellectual disability and psychiatric disorders also may be present ◦Autosomal recessive - chromosome 21 ◦Treatment - Vitamin B6, folic acid, betaine, dietary restrictions ◦Diagnosis - heel stick on new-born babies within 48 hours of birth ◦Levels 5-15 uM ◦Symptoms of homocystunuria are very similar to Marfan's syndrome ‣ Fibrillin-1 in connective tissues is disrupted ◦Elevated plasma homocysteine is associated with cardiovascular disease ◦CBS involved in gasotransmitter hydrogen sulphide synthesis