Heme synthesis and use. The heme synthetic pathway and heme’s intracellular trafficking are diagrammed. The first and rate-limiting step is catalyzed by ALAS. ALAS2 is the erythroid-specific ALAS isoform (red). The presence of an iron responsive element (IRE) in the 5′ untranslated region of ALAS2 mRNA renders it exquisitely sensitive to iron. All other cells, including hepatocytes, contain ALAS1 (blue). CEP results from mutation of UROS, the fourth enzyme of the heme synthetic pathway. Other porphyrias result from mutations of other heme synthetic pathway enzymes, eg, HMBS (hydroxymethylbilane synthase; acute intermittent porphyria), UROD (uroporphyrinogen decarboxylase; porphyria cutanea tarda), CPOX (coproporphyrinogen oxidase; hereditary coproporphyria), PPOX (protoporphyrinogen oxidase; variegate porphyria), and FECH (ferrochelatase; erythropoietic protoporphyria). Iron chelation ameliorates CEP by reducing ALAS2 translation, thus decreasing heme synthesis and the buildup of pathway intermediates proximal to UROS and their phototoxic metabolites. ER, endoplasmic reticulum; Hgb, hemoglobin. Professional illustration by Patrick Lane, ScEYEnce Studios.