Amino acid metabolism

Amino acids: essential, glucogenic, ketogenic

• Essential (cannot be made by humans): phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, histidine, leucine and lysine. Arginine is conditionally essential in growth; tyrosine becomes essential in PKU.
• Purely ketogenic: leucine and lysine (their carbon skeletons give only acetyl-CoA or acetoacetate). Both ketogenic and glucogenic: phenylalanine, tyrosine, tryptophan, isoleucine, threonine. All others are glucogenic.
• Acidic: aspartate, glutamate. Basic: lysine, arginine, histidine (its imidazole group buffers near physiological pH). Sulphur-containing: methionine, cysteine.

Protein quality and requirement

• A protein's quality depends on how well its essential amino acid pattern matches human needs. Cereals such as wheat are low in lysine; pulses such as lentils are low in methionine. Eating daal with roti supplies each other's limiting amino acid (complementary proteins), so the mixture has higher biological value than either alone.
• Egg and milk proteins have the highest biological value.
• Healthy adult requirement: about 0.8 g of protein per kg body weight per day, more in pregnancy, lactation, growth and illness.
• Nitrogen balance is positive in growth, pregnancy and recovery; negative in starvation, burns, sepsis and after major trauma even with normal intake.

Hormonal control of muscle protein

• Insulin is the most powerful stimulus of muscle protein synthesis and inhibitor of protein breakdown after a meal (with amino acids, especially leucine, acting through mTOR). Untreated type 1 diabetes causes muscle wasting despite eating.
• Cortisol, glucagon and catecholamines are catabolic: cortisol breaks down muscle protein to supply amino acids for gluconeogenesis.
• In disuse and cachexia, atrophy results from reduced synthesis and increased breakdown through the ubiquitin–proteasome pathway (and autophagy).

Removing nitrogen

• Transamination moves the amino group to alpha-ketoglutarate to form glutamate; aminotransferases (ALT, AST) need pyridoxal phosphate (B6).
• Oxidative deamination by glutamate dehydrogenase in liver mitochondria releases free ammonia.
• Ammonia travels from tissues as glutamine and from muscle as alanine (glucose–alanine cycle).

Urea cycle

• Urea's two nitrogens come from free ammonia and aspartate. The cycle uses 3 ATP (4 high-energy bonds) and links to the citric acid cycle through fumarate.

Hyperammonaemia

• Causes: liver failure, portosystemic shunting, urea cycle defects, valproate.
• Ammonia drains alpha-ketoglutarate from the brain's citric acid cycle and raises glutamine in astrocytes, which swell: cerebral oedema, vomiting, asterixis, encephalopathy.
• Ornithine transcarbamylase deficiency: the commonest urea cycle disorder, X-linked; hyperammonaemia with high orotic acid (carbamoyl phosphate spills into pyrimidine synthesis) but no megaloblastic anaemia, unlike hereditary orotic aciduria.
• Treatment: limit protein, lactulose, rifaximin, sodium benzoate or phenylbutyrate (alternative nitrogen excretion), arginine.

Products made from amino acids

• Catecholamines: tyrosine hydroxylase (rate-limiting) makes DOPA; DOPA decarboxylase (B6) makes dopamine; dopamine beta-hydroxylase (vitamin C) makes noradrenaline; PNMT (induced by cortisol) makes adrenaline.
• Creatinine forms non-enzymatically from creatine phosphate at a rate proportional to muscle mass.

Inborn errors of amino acid metabolism

• Maternal PKU: if a woman with PKU stops her diet, high maternal phenylalanine crosses the placenta and damages a fetus who does not have PKU: microcephaly, intellectual disability, growth restriction and congenital heart defects. Strict diet must restart before conception.
• Ochronotic arthropathy in alkaptonuria: homogentisic acid polymer deposits in cartilage cause degenerative arthritis of the spine and large joints from middle age, with disc calcification on X-ray.
• Generalised aminoaciduria with glycosuria, phosphaturia and bicarbonate loss indicates Fanconi syndrome (proximal tubule failure), not a single transporter defect.
• PKU is among the commonest inborn errors detected on newborn screening.

Remember Leucine and lysine are purely ketogenic; urea's nitrogens come from ammonia and aspartate.

Exam trap Homocystinuria dislocates the lens downward and causes thrombosis; Marfan syndrome dislocates it upward.

Exam trap A baby without PKU can still be damaged by its mother's uncontrolled PKU.

How FCPS asks about this

• Why daal with roti improves protein quality: each supplies the amino acid the other lacks (lysine, methionine).
• Daily adult protein requirement: about 0.8 g/kg.
• Pregnant woman off her PKU diet: risk of microcephaly and heart defects in the baby.
• Back pain in alkaptonuria: ochronotic arthropathy.
• Strongest hormonal stimulus of muscle protein synthesis: insulin.
• Second amino acid feeding nitrogen into the urea cycle: aspartate.
• Burnt-sugar urine with neonatal encephalopathy: maple syrup urine disease, branched-chain alpha-keto acid dehydrogenase.