PathwayStep2620 PathwayStep2609 PathwayStep2608 PathwayStep2607 PathwayStep2617 PathwayStep2616 PathwayStep2619 PathwayStep2618 PathwayStep2613 PathwayStep2612 PathwayStep2615 PathwayStep2614 PathwayStep2611 PathwayStep2610 Heme biosynthesis Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Eight enzymes are involved in heme biosynthesis, four each in the mitochondria and the cytosol. The process starts in the mitochondria with the condensation of succinyl CoA (from the TCA cycle) and glycine to form 5-aminolevulinate (ALA). The next four steps take place in the cytosol. Two molecules of ALA are condensed to form the monopyrrole porphobilinogen (PBG). The next two steps convert four molecules of PBG into the cyclic tetrapyrrole uroporphyringen III, which is then decarboxylated into coproporphyrinogen III. The last three steps occur in the mitochondria and involve modifications to the tetrapyrrole side chains and finally, insertion of iron. In addition to these synthetic steps, a spontaneous cytosolic reaction allows the formation of uroporphyringen I which is then enzymatically decarboxylated to coproporphyrinogen I, which cannot be metabolized further in humans. Also, lead can inactivate ALAD, the enzyme that catalyzes PBG synthesis, and ferrochelatase, the enzyme that catalyzes heme synthesis.<br>The porphyrias are disorders that arise from defects in the enzymes of heme biosynthesis. Defective pathway enzymes after ALA synthase result in accumulated substrates which can cause either skin problems, neurological complications, or both due to their toxicity in higher concentrations. They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction of the substrate. Each defect is described together with the reaction it affects. GENE ONTOLOGYGO:0006783 Pubmed10522552 Pubmed16839620 Reactome Database ID Release 43189451 Reactome, http://www.reactome.org ReactomeREACT_9465 Reviewed: Sassa, S, 2007-01-24 10:18:36 Oxidation of protoporphyrinogen IX to protoporphyrin IX Uroporphyrinogen III is decarboxylated to form coproporphyrinogen III Uroporphyrinogen I is decarboxylated to form coproporphyrinogen I Translocation of coproporphyrinogen III from the cytosol to the mitochondrial intermembrane space Conversion of coproporphyrinogen III to protoporphyrinogen IX Two molecules of ALA condense to form porphobilinogen (PBG) Four PBGs combine through deamination to form hydroxymethylbilane (HMB) Conversion of HMB to uroporphyrinogen III Spontaneous conversion of HMB to uroporphyrinogen I ALAD octamer associates with Pb++, forming a catalytically inactive complex Protoporphyrin IX is transported from the mitochondrial intermembrane space into the mitochondrial matrix Ferrous iron is inserted into protoporphyrin IX to form heme ALA is transported from the mitochondrial matrix to the cytosol Succinyl CoA and glycine condense to form 5-aminolevulinate (ALA)