Solvent isotope effects in the catalytic cycle of P450 CYP17A1: Computational modeling of the hydroxylation and lyase reactions.

ABSTRACT: The catalytic cycle of the cytochromes P450 (CYP) requires two electrons from a protein redox partner and two protons from water to generate the main catalytic intermediate, a ferryl-oxo complex with π-cation on the heme porphyrin ring, termed Compound 1. The protonation steps are at least partially rate-limiting, therefore the steady-state rates of P450 catalysis are usually slower in deuterated solvent (D₂O) by a factor of 1.5-3. However, in several P450 systems a pronounced inverse kinetic solvent isotope effect (KSIE ∼0.4-0.7) is observed, where the reaction is faster in D₂O. This raises an important mechanistic question: Is this inverse solvent isotope effect compatible with Compound 1 catalyzed reactions, or is it indicative of another catalytic intermediate bei

SUBMITTER: Denisov IG 

PROVIDER: S-EPMC10128154 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature