Protein Metabolism

Proteins are not stored by the body in the same way as fats or carbohydrates; thus, there is a constant turnover. Dietary proteins are digested into amino acids in the gastrointestinal tract and absorbed. Intracellularly, protein degradation occurs via the ubiquitin-proteasome pathway or lysosomal digestion. Amino acid catabolism begins with transamination, usually transferring the amino group to alpha-ketoglutarate to form glutamate, catalyzed by aminotransferases (ALT/AST). Glutamate then undergoes oxidative deamination by glutamate dehydrogenase to release free ammonia. Because ammonia is highly toxic,尤其 to the central nervous system, it is converted into urea in the liver via the urea cycle and subsequently excreted by the kidneys. The remaining carbon skeletons are classified as glucogenic (can be converted to glucose via gluconeogenesis) or ketogenic (converted to acetyl-CoA or ketone bodies). During starvation, muscle protein breakdown provides the primary substrate for gluconeogenesis to maintain blood glucose for the brain. Disorders of this system include urea cycle defects and aminoacidurias like Phenylketonuria (PKU).

The primary step in amino acid catabolism is the removal of the alpha-amino group by transamination. AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) transfer the amino group to alpha-ketoglutarate, forming glutamate and a keto-acid. These enzymes require Pyridoxal Phosphate (B6) as a cofactor. In the liver, glutamate is deaminated back to alpha-ketoglutarate, releasing NH4+. The Urea Cycle then processes NH4+. It begins in the mitochondria with the formation of carbamoyl phosphate (requiring 2 ATP and N-acetylglutamate as an activator). This reacts with ornithine to form citrulline, which moves to the cytosol. Further reactions involve aspartate and produce argininosuccinate, then arginine and fumarate. Finally, arginase cleaves arginine into urea and ornithine, which restarts the cycle. Regarding the carbon skeletons: all amino acids except leucine and lysine can be glucogenic. Some, like phenylalanine and tyrosine, are both. PKU results from a deficiency in phenylalanine hydroxylase, preventing the conversion of phenylalanine to tyrosine, leading to the accumulation of toxic phenylketones.

Hyperammonaemia is a medical emergency, presenting with lethargy, vomiting, and cerebral oedema; it is commonly seen in end-stage liver disease or urea cycle defects. Elevated transaminases (ALT/AST) are markers of hepatocellular injury. PKU is screened for at birth (Guthrie test); if untreated, it causes severe intellectual disability. In clinical practice, negative nitrogen balance (where nitrogen excretion exceeds intake) is seen in trauma, sepsis, and starvation, indicating muscle wasting. Conditions like Alkaptonuria (black urine) and Maple Syrup Urine Disease (sweet-smelling urine) are rare but high-yield disorders of protein metabolism.

Key tests include: Serum Ammonia (high in liver failure/urea cycle defects), LFTs (ALT/AST), Plasma Amino Acids (to diagnose PKU or MSUD), and Urine Organic Acids. BUN (Blood Urea Nitrogen) is a marker of renal function and protein breakdown. Newborn screening (heel prick) is standard in the UK for PKU.

Management of hyperammonaemia involves protein restriction and ammonia-scavenging drugs (e.g., sodium benzoate). In PKU, a lifelong low-phenylalanine diet with tyrosine supplementation is required. For liver-related metabolic failure, lactulose is used to reduce ammonia absorption in the gut. Acute management of metabolic crises in children requires IV glucose to stop catabolism.