Heme Biosynthesis in Red Cell Precursors. Heme biosynthesis begins in the mitochondrial matrix with condensation of glycine and succinyl-CoA by ALA synthase, forming δ–aminolevulinic acid (ALA). Truncations or mutations in the C-terminal part of the erythroid-specific form of ALA synthase (ALA-S2) lead to X-linked erythropoietic protoporphyria (EPP), while inactivating mutations cause X-linked sideroblastic anemia. ALA is transported out of the mitochondria to the cytoplasm were steps ii-v of the pathway occur. Each of these steps involves an enzyme that when mutated causes a specific type of porphyria. (Please see the online version of this figure legend for the name and function of each enzyme and the type of porphyria that results when the enzyme is mutated [or inhibited, as is the case with sporadic porphyria cutanea tarda, step v].) After step v, coproporphyrinogen III is moved across the outer mitochondrial membrane to the intermembrane space where coproporphyrinogen III oxidase (CPO) decarboxylates two of the four propionates to vinyl groups, (defects in this step lead to hereditary coproporphyria) forming protoporphyrinogen IX (PP-gen). Protoporphyrinogen oxidase (PPO), the penultimate enzyme in the pathway, oxidizes PP-gen to protoporphyrin IX (PPIX) on the matrix side of the inner mitochondrial membrane (mutations affecting PPO are the genetic basis of variegate porphyria). The final step in the pathway is insertion of iron (Fe2+) into PPIX by ferrochelatase (FECH), producing heme. Defects in FECH are responsible for the autosomal recessive variant of EPP. The Fe2+ is delivered to FECH by mitoferrin 1 (MFRN1), which is stabilized by ABCb10. For stability and function, FECH requires a 2Fe-2S cluster prosthetic group, a product of the iron sulfur cluster (ISCU) machinery.