Ferrochelatase catalyzes the metallation of protoporphyrin IX in the terminal step of heme biosynthesis. Mutations in the ferrochelatase gene can lead to the disease erythropoietic porphyria. The catalyzing mechanism of ferrochelatase is still not fully understood. In this paper, we have studied the insertion of Fe2+ into the protoporphyrin IX ring by Bacillus subtilis ferrochelatase using combined quantum mechanical and molecular mechanics (QM/MM) calculations. Geometries were optimized at the BP86/6-31G* level and energies were calculated at the B3LYP/TZVP level. The overall process involves the step-wise displacement of Glu-264, His-183, and a water molecule from Fe2+, and the removal of two protons from the porphyrin ring. The rate-determining step is the cleavage of the bond between the oxygen atom of Glu-264 and Fe2+, concomitant with the formation of the first Fe-N bond. It has an energy barrier of 57 kJ mol(-1). The porphyrin ring is only slightly distorted in the enzyme active site. The residue Tyr-13 plays a key role for the catalytic process extracting two protons from protoporphyrin IX. (C) 2009 Elsevier Inc. All rights reserved.
Bibliographical noteThe information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
Subject classification (UKÄ)
- Biochemistry and Molecular Biology
- Protoporphyrin IX