A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study.

Abstract

The intriguing deactivation of the cytochrome P450 (CYP) 2B4 enzyme induced by mutation of a single residue, Phe429 to His, is explored by quantum mechanical/molecular mechanical calculations of the O-OH bond activation of the (Fe(3+)OOH)(-) intermediate. It is found that the F429H mutant of CYP 2B4 undergoes homolytic instead of heterolytic O-OH bond cleavage. Thus, the mutant acquires the following characteristics of a heme oxygenase enzyme: (a) donation by His429 of an additional NH---S H-bond to the cysteine ligand combined with the presence of the substrate retards the heterolytic cleavage and gives rise to homolytic O-OH cleavage, and (b) the Thr302/water cluster orients nascent OH(•) and ensures efficient meso hydroxylation.

DOI: 10.1021/ja211905e

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Cite this paper

@article{Usharani2012ASM, title={A single-site mutation (F429H) converts the enzyme CYP 2B4 into a heme oxygenase: a QM/MM study.}, author={Dandamudi Usharani and Costantino Zazza and Wenzhen Lai and Mukesh Chourasia and Lucy A Waskell and Sason Shaik}, journal={Journal of the American Chemical Society}, year={2012}, volume={134 9}, pages={4053-6} }