InterPro: IPR019772 Ferrochelatase, active site

Synonym(s): Protohaem ferro-lyase, Iron chelatase, etc.

Ferrochelatase catalyses the last step in haem biosynthesis: the chelation of a ferrous ion to proto-porphyrin IX, to form protohaem [1, 2]. In eukaryotic cells, it binds to the mitochondrial inner membrane with its active site on the matrix side of the membrane.

The X-ray structure of Bacillus subtilis and human ferrochelatase have been solved [3, 4]. The human enzyme exists as a homodimer. Each subunit contains one [2Fe-2S] cluster. The monomer is folded into two similar domains, each with a four-stranded parallel beta-sheet flanked by an alpha-helix in a beta-alpha-beta motif that is reminiscent of the fold found in the periplasmic binding proteins. The topological similarity between the domains suggests that they have arisen from a gene duplication event. However, significant differences exist between the two domains, including an N-terminal section (residues 80-130) that forms part of the active site pocket, and a C-terminal extension (residues 390-423) that is involved in coordination of the [2Fe-2S] cluster and in stabilisation of the homodimer.

Ferrochelatase seems to have a structurally conserved core region that is common to the enzyme from bacteria, plants and mammals. Porphyrin binds in the identified cleft; this cleft also includes the metal-binding site of the enzyme. It is likely that the structure of the cleft region will have different conformations upon substrate binding and release [3].

The signature pattern for this enzyme is based on a conserved region which contains a conserved histidine (H263) that is one of the active site residues. The mutation H263A resulted in total loss of activity in human ferrochelatase activity. Mutants D340E, E343D and H341C result in diminished activity [4].