Ferrochelatase

Abstract

Ferrochelatase, the terminal enzyme of the heme biosynthetic pathway, catalyzes the insertion of ferrous iron into protoporphyrin IX. It is encoded by a single gene, and mutations in the human gene are associated with the inherited disorder, erythropoietic protoporphyria. With the development of heterologous overexpression systems and the ready availability of recombinant ferrochelatase, new structural elements have been identified and new aspects of the ferrochelatase-catalyzed reaction mechanism have been unraveled. Namely, a [2Fe–2S] cluster is a prosthetic group in mammalian ferrochelatase, a conserved and essential histidine residue appears to be involved in the binding of the metal substrate and a conserved glutamate residue has been proposed to have a catalytic role. The three-dimensional structure for Bacillus subtilis ferrochelatase, the only known ‘water-soluble’ ferrochelatase, revealed that the protein contains two similar domains, each of which has a four-stranded β-sheet flanked by α-helices; the active site was modeled to be in a cleft defined by the two domains. The definition of the structure and catalytic mechanism of ferrochelatase should help in the interpretation of the impact caused by erythropoietic porphyria mutations.