In situ conversion of coproporphyrinogen to heme by murine mitochondria: Terminal steps of the heme biosynthetic pathway

Abstract

Coproporphyrinogen oxidase (EC 1.3.3.3), protoporphyrinogen oxidase (EC 1.3.3.4), and ferrochelatase (EC 4.99

Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

“…22 Because Fech is present at the convergence of protoporphyrin IX and iron import pathways to produce heme, 2 and Mfrn1 forms higher-order protein complexes 8 that are much larger than predicted for an Mfrn1-Abcb10-Fech complex, it is rational to anticipate that Mfrn1-Abcb10-Fech could form larger complexes with other heme biosynthetic pathway enzymes. Indeed, a model proposing an interaction between the terminal 3 of heme biosynthetic enzymes has been forwarded, 23 and data in support of a complex between PPO and Fech have been presented. 4,23,24 Such a complex could coordinate the correct molar ratio and sufficient, but not excessive, supply of protoporphyrin IX and Fe 2ϩ substrates for Fech to produce heme.…”

“…Indeed, a model proposing an interaction between the terminal 3 of heme biosynthetic enzymes has been forwarded, 23 and data in support of a complex between PPO and Fech have been presented. 4,23,24 Such a complex could coordinate the correct molar ratio and sufficient, but not excessive, supply of protoporphyrin IX and Fe 2ϩ substrates for Fech to produce heme. 6,25 …”

Production and characterization of erythropoietic protoporphyric heterodimeric ferrochelatases

“…29 In addition, it has been proposed, based on kinetic and structural approaches, that ferrochelatase interacts at least transiently with protoporphyrinogen oxidase (PPO), the penultimate enzyme in the pathway. 15,30,31 Thus, the spatial orientation of an EPP mutation might have an impact on enzyme catalysis, structural stability, or interactions with frataxin or PPO. The phenotype and clinical presentation of these various classes of mutations could be profoundly different and may explain some of the diverse published observations for EPP patients.…”

Illuminating the black box of B 12 biosynthesis

“…Second is the observation that a mixture containing all pathway enzymes functions more effectively than individual enzymes to produce product. This finding is not unlike what has been reported for siroheme biosynthesis (7,11) and hinted at for protoheme synthesis (12). Given the reactivity of tetrapyrrole biosynthetic pathway intermediates, it is not a surprise that evolution has designed pathway enzymes to hold on to products until downstream acceptors are available.…”

“…Dietary folate supplementation can ameliorate the anemia, but not myelin damage or accumulation of homocysteine (homocysteinuria), which may contribute to stroke and cardiac infarction. Because most nonvegetarian diets provide a reasonable source of B 12 , deficiency of cobalamin in metazoans generally results from defects in digestion, absorption, or transport mechanisms, although intestinal infestation with the fish tapeworm Diphyllobothrium latum, which competes for B 12 , may also result in megaloblastic anemia. Strict vegans or life-long vegetarians may need to consider B 12 supplementation because plants contain no cobalamin (10).…”