Although heme is synthesised in virtually all tissues, the principal sites of synthesis are erythroid cells (~85%) and hepatocytes (most of the remainder). Eight enzymes are involved in heme biosynthesis, four each in the mitochondria and the cytosol (Layer et al. 2010). 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 (Ponka et al. 1999, Aijoka et al. 2006).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 (Peoc'h et al. 2016).
Heinz, DW, Jahn, D, Layer, G, Reichelt, J
Phillips, JD, Ajioka, RS, Kushner, JP
Deybach, JC, Puy, H, Peoc'h, K, Talbi, N, Gouya, L, Martin-Schmitt, C
Ponka, P
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