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

Dandamudi Usharani, Costantino Zazza, Wenzhen Lai, Mukesh Chourasia, Lucy Waskell*, Sason Shaik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)4053-4056
Number of pages4
JournalJournal of the American Chemical Society
Volume134
Issue number9
DOIs
StatePublished - 7 Mar 2012

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