--- module: 090-01 language: en chapter: 90 title: "Amino-Acid, Nitrogen, Haem, and Nucleotide Metabolism" module_title: "Protein turnover, amino-acid catabolism, ammonia transport, and the urea cycle" source_sha256: 60e6e0d40f37b0431c9abb22ad8e0762c1e36c5006371a6e2ffb2b2a7124a6eb --- # Protein turnover, amino-acid catabolism, and the urea cycle ## Protein turnover and balance ### No inert storage depot for amino acids #### Nitrogen excreted, carbon to shared pathways ### Proteasome: short-lived, regulatory, abnormal proteins ### Autophagy-lysosome: long-lived, aggregates, organelles ### Positive in growth, pregnancy, recovery ### Negative in starvation, illness, trauma, immobility ### Nitrogen balance misses unmeasured routes #### Stable muscle mass can hide altered turnover ## Digestion and absorption ### Gastric acid denatures, pepsin cleaves ### Pancreatic zymogens activated in small intestine #### Enteropeptidase initiates trypsin #### Trypsin activates other enzymes ### Brush-border and intracellular peptidases finish ### Sodium- or proton-coupled uptake to portal blood ### Transporter defects hit intestine, kidney, or both #### Neutral amino-acid loss: pellagra-like features #### Cystine and dibasic loss: cystine stones ## Transamination and deamination ### Amino group moved to alpha-ketoglutarate #### Forms glutamate and an alpha-ketoacid #### Pyridoxal phosphate carries the amino group ### Alanine aminotransferase relatively liver enriched ### Aspartate aminotransferase in liver, muscle, heart #### Plasma activity shows leakage, not function ### Glutamate as central nitrogen collector #### Glutamate dehydrogenase releases free ammonia #### Regulated by energy-state nucleotides ### Transdeamination: transfer, then deamination ## Ammonia transport ### Free ammonia is toxic to brain ### Glutamine synthetase fixes ammonia using ATP ### Liver and kidney glutaminase release ammonia #### For urea synthesis or urinary buffering ### Gut ammonia reaches liver via portal blood ### Glucose-alanine cycle from muscle #### Supports glucose but costs muscle protein ### Glutamine fuels gut, immune cells, kidney ## Urea cycle ### Spans mitochondrial matrix and cytosol ### Nitrogen from ammonia and aspartate ### Three ATP, four high-energy bonds ### Carbamoyl-phosphate synthetase one #### N-acetylglutamate is obligatory activator #### Arginine and amino-acid load raise it ### Ornithine transcarbamylase forms citrulline ### Argininosuccinate synthetase adds aspartate ### Lyase yields arginine and fumarate ### Arginase releases urea and ornithine ### Fumarate links to citric-acid metabolism #### Aspartate-argininosuccinate shunt ### Urea excreted mainly by kidney ## Urea-cycle defects ### Hyperammonaemia after protein, illness, fasting #### Vomiting, confusion, seizures, coma #### Early respiratory alkalosis ### Neonates first normal after maternal clearance ### Ornithine-transcarbamylase deficiency is X-linked #### Variable X inactivation in females #### Carbamoyl phosphate spills, orotic acid rises ### Proximal defects: no similar orotic acid rise ### Arginase deficiency: chronic spasticity #### Ammonia rise may be milder ### Interpret by age, feeding, treatment, timing ## Management and brain injury ### Stop protein briefly ### Glucose and lipid reverse catabolism ### Nitrogen scavengers form excretable conjugates ### Dialysis for severe levels or encephalopathy ### Long term: protein for growth, avoid excess ### Astrocyte glutamine causes osmotic stress #### Transmitter pools, mitochondria, blood flow disturbed ### Plasma level correlates imperfectly with symptoms ## Liver, kidney, and sampling ### Hepatic encephalopathy differs from inherited defects #### Portal shunting, inflammation, drugs, electrolytes #### Normal ammonia does not exclude it ### Kidney makes ammonium and bicarbonate from glutamine #### Acidosis increases renal glutamine use #### Urinary ammonium is adaptive acid excretion ### Warm or delayed samples raise ammonia #### Repeat promptly, but treat if delay is unsafe ## Carbon skeletons ### Glucogenic, ketogenic, or both ### Leucine and lysine exclusively ketogenic ### Fate set by hormones, tissue, demand ### Branched-chain transamination mainly in muscle #### Thiamine-dependent decarboxylation complex #### Defect: maple-syrup-urine disease #### Limit branched substrates, preserve growth