--- module: 090-02 language: en chapter: 90 title: "Amino-Acid, Nitrogen, Haem, and Nucleotide Metabolism" module_title: "One-carbon metabolism, haem synthesis, bilirubin, and specialised amino-acid products" source_sha256: b4891fd88d260347968158fb8a41362c87d4a87a6085327af96a022a2dbbf1c1 --- # One-carbon metabolism, haem, bilirubin, and amino-acid products ## Folate one-carbon cycle ### Tetrahydrofolate carries one-carbon units ### Serine hydroxymethyltransferase forms glycine ### Methylene form supports thymidylate synthesis ### Reduced to methyl tetrahydrofolate ### Methionine synthase needs vitamin B12 #### B12 deficiency traps folate as methyl form #### Nucleotide synthesis fails despite total folate ## Methylation and transsulfuration ### S-adenosylmethionine is the main methyl donor ### Methylates DNA, RNA, proteins, phospholipids ### Plasma homocysteine cannot show methylation potential ### Cystathionine beta-synthase starts transsulfuration #### Cysteine for glutathione, taurine, sulfate #### Severe deficiency: homocystinuria ##### Thrombosis, lens dislocation, skeletal change ### Mild hyperhomocysteinaemia from vitamins, kidney #### Vitamin lowering has not uniformly cut events ## Folate and B12 deficiency ### Folate lack impairs thymidylate and purines #### Megaloblastic haematopoiesis #### Gut and fetal tissues affected ### B12 lack also impairs methylmalonyl-CoA mutase #### Methylmalonate rises, nerves injured ### Folate alone may let neuropathy progress ## Haem synthesis ### Ferrous iron in protoporphyrin ring ### Begins and ends in mitochondria ### Aminolevulinate synthase: glycine, succinyl-CoA #### Hepatic form repressed by haem, induced by drugs #### Erythroid form follows iron and globin #### B6 deficiency: sideroblastic anaemia ### Zinc-dependent dehydratase forms porphobilinogen ### Uroporphyrinogen, then coproporphyrinogen ### Ferrochelatase inserts ferrous iron ## Lead and porphyrias ### Lead inhibits dehydratase and ferrochelatase #### Anaemia with basophilic stippling #### Blood lead and exposure history central ### Early precursors: acute neurovisceral attacks #### Abdominal pain, neuropathy, hyponatraemia #### Drugs, fasting, alcohol induce haem demand ### Later porphyrins: light-dependent skin injury #### Urine, plasma, stool, red-cell patterns #### Protect samples from light ### Suppress precursors, remove iron, avoid triggers ## Bilirubin ### Haem oxygenase opens ring to biliverdin ### Unconjugated bilirubin bound to albumin ### UDP-glucuronosyltransferase conjugates in liver ### Gut microbes form urobilinogen products #### Brown stercobilin in stool #### Small amount becomes urinary urobilin ### Unconjugated excess not filtered into urine ### Conjugated excess: excretion failure, cholestasis #### Dark urine, pale stool ### Neonatal risk of kernicterus #### More production, immature conjugation, recycling #### Phototherapy makes excretable isomers ## Tyrosine and tryptophan products ### Phenylalanine hydroxylation forms tyrosine ### Catecholamines, thyroid hormones, melanin #### Tyrosine hydroxylase is rate-controlling ### Phenylketonuria disrupts brain development #### Early diet prevents intellectual disability #### Tetrahydrobiopterin defects need transmitter therapy ### Tryptophan forms serotonin, then melatonin #### Carcinoid diverts tryptophan: niacin deficiency ## Histamine, GABA, and nitric oxide ### Histidine decarboxylation forms histamine #### Allergy, gastric acid, wakefulness ### Glutamate decarboxylation forms GABA ### Arginine forms nitric oxide and citrulline #### Endothelial, neuronal, inducible isoforms #### Low cofactors uncouple, making superoxide ## Creatine, glutathione, and melanin ### Creatine from arginine, glycine, methyl group #### Creatine kinase buffers rapid energy demand #### Plasma creatinine reflects breakdown, kidney ### Glutathione: glutamate, cysteine, glycine #### Detoxifies peroxides, conjugates electrophiles #### Cysteine limits synthesis: N-acetylcysteine ### Tyrosinase starts melanin in melanosomes #### Albinism: multiple molecular disorders #### Vision affected via retinal development