title: 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.
authors.affiliation: Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Dandamudi
authors.initials: D
authors.lastname: Usharani
authors.forename: Costantino
authors.initials: C
authors.lastname: Zazza
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Lai
authors.forename: Mukesh
authors.initials: M
authors.lastname: Chourasia
authors.forename: Lucy
authors.initials: L
authors.lastname: Waskell
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016296:Mutagenesis; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011789:Quantum Theory
chemical_list: D050505:Mutant Proteins; D001189:Aryl Hydrocarbon Hydroxylases; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit); D006419:Heme Oxygenase (Decyclizing)