Journal
SCIENCE
Volume 342, Issue 6160, Pages 825-829Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1244373
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Funding
- NIH [R01-GM101390]
- DOE Office of Biological and Environmental Research
- NIH National Institute of General Medical Sciences [P41GM103393]
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Cytochrome P450 enzymes activate oxygen at heme iron centers to oxidize relatively inert substrate carbon-hydrogen bonds. Cysteine thiolate coordination to iron is posited to increase the pK(a) (where K-a is the acid dissociation constant) of compound II, an iron(IV)hydroxide complex, correspondingly lowering the one-electron reduction potential of compound I, the active catalytic intermediate, and decreasing the driving force for deleterious auto-oxidation of tyrosine and tryptophan residues in the enzyme's framework. Here, we report on the preparation of an iron(IV) hydroxide complex in a P450 enzyme (CYP158) in >= 90% yield. Using rapid mixing technologies in conjunction with Mossbauer, ultraviolet/visible, and x-ray absorption spectroscopies, we determine a pK(a) value for this compound of 11.9. Marcus theory analysis indicates that this elevated pK(a) results in a >10,000-fold reduction in the rate constant for oxidations of the protein framework, making these processes noncompetitive with substrate oxidation.
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