Albertine Donker

Chapter 1 24 Figure 4. Heme Biosynthesis consists of eight enzymatic reactions in both the mitochondria and cytosol and is regulated by the activity of ALAS2 MFRN1 FLVCR1b HEME FECH ABCB10 PPOX Fe Protoporphyrin IX Protoporphyrinogen IX Coproporphyrinogen III ABCB6 ? 7 6 2 3 4 5 ALA Porphobilinogen Hydroxymethylbilane Uroporphyrinogen III Coproporphyrinogen III UROS UROD Cytosol Intermembrane space of mitochondrium 1 8 Succinyl-CoA Glycine ALAS2 ALA SLC25A38 ABCB10 Pyridoxal 5 phosphate* Mitochondrium ALAD HMBS CPOX The heme biosynthetic pathway consists of eight enzymatic steps; two reactions take place inside the mitochondria and six inside the cytosol or the intermembrane space of the mitochondria. The first and rate-limiting step of heme synthesis occurs in the mitochondrial matrix with the condensation of succinyl- CoA and glycine by ALAS2 to generate ALA. Pyridoxal 5-Phosphate (vitamin B6) is required as a cofactor in this enzymatic reaction ( 1 ). It has been hypothesized that SLC25A38 facilitates ALA production by importing glycine into mitochondria or by exchanging glycine for ALA across the mitochondrial inner membrane. Both SLC25A38 and ABCB10 have been proposed as mitochondrial ALA exporters. After ALA has been transported out of the mitochondria, it is converted to coproporphyrinogen III by four enzymatic reactions inside the cytosol ( 2-5 ). ALAD catalyzes the condensation of two molecules of ALA to form one molecule of porphobilinogen ( 2 ). Next, HMBS catalyzes the synthesis of four porphobilinogen molecules to form the linear hydroxymethylbilane ( 3 ) that is converted to uroporphyrinogen III by UROS ( 4 ). The last cytoplasmic step, the synthesis of coproporphyrinogen III ( 5 ), is catalyzed by UROD. Coproporphyrinogen III is then transported back into the mitochondrial intermembrane space, possibly via ABCB6, where it is converted to protoporphyrinogen IX by CPOX ( 6 ). The next step is the conversion of protoporphyrinogen IX to protoporphyrin IX by PPOX and its transport into the matrix of the mitochondria ( 7 ). Inside the mitochondria, Fe+2 that is imported by ABCB10 and MFRN1, is incorporated into protoporphyrin IX by FECH to generate heme, which is the last step of heme biosynthesis ( 8 ). FLVCR1b may mediate the transfer of heme out of the mitochondria. Abbreviations: ABCB denotes ATP Binding Cassette Subfamily B; ALA, Aminolevulinic acid; ALAD, aminolevulinate dehydratase; ALAS2, 5-Aminolevulinic acid synthase 2; CPOX, coproporphyrinogen oxidase; FECH, ferrochelatase; FLVCR1, Feline leukemia virus subgroup C receptor 1b; HMBS, hydroxymethylbilane synthase; MFRN, mitoferrin; PPIX, protoporphyrin IX; PPOX, protoporphyrinogen oxidase; SLC25A38, Solute carrier 25A38; UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen synthase. Figure adapted from Chiabrando et al , 2014. 55