Molecular and genetic characterization of ferrochelatase.

Abstract

Ferrochelatase (heme synthase, protoheme ferrolyase [EC 4.99.1.1]), the final enzyme of the heme biosynthetic pathway, catalyzes the insertion of ferrous ion into protoporphyrin IX to produce protoheme IX. The thorough understanding of the enzyme is prerequisite to elucidating the regulation of iron and heme metabolism. The enzyme's activity is found on the inner mitochondrial membrane of a variety of mammalian cells. The enzyme catalyzes the chelation not only of iron but also of divalent metal ions including cobalt and zinc, and the activity is affected by various metals and lipids. The molecular weights of eukaryotic ferrochelatases are 40,000-42,000 daltons. Complementary DNA (cDNA) encoding ferrochelatase from mouse, human, yeast and bacteria have been isolated, and the derived amino acid sequences show 27-88% homologies among species. The expression of ferrochelatase seems to occur in all living cells, and to play an important role in the regulation of heme biosynthesis. Ferrochelatase is markedly induced at the transcriptional level during erythroid differentiation when iron uptake by cells and hemoglobin synthesis are upregulated. This induction can be explained by the existence of sequences characteristic of erythroid-related genes. The gene has been mapped to human chromosome 18q21.3 and contains 11 exons with a size of about 45 kilobases. Once the gene for human ferrochelatase is cloned, the molecular basis and clinical diagnosis of erythropoietic protoporphyria, caused by a deficiency of ferrochelatase, will become possible. This review summarizes recent advances in ferrochelatase research and suggests important subjects for future research.