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Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions.

Guengerich FP
Methods Enzymol. 2017 596: 217-238

PMID: 28911772 · PMCID: PMC5776663 · DOI:10.1016/bs.mie.2017.06.036

Cytochrome P450 (P450, CYP) research provides many opportunities for the application of kinetic isotope effect (KIE) strategies. P450s collectively catalyze oxidations of more substrates than any other group of enzymes, and CH bond cleavage is a major feature in a large fraction of these reactions. The presence of a significant primary deuterium KIE is evidence that hydrogen abstraction is at least partially rate-limiting in the reactions, and this appears to be the case in many P450 reactions. The first report of a KIE in (P450-linked) drug metabolism appeared in 1961 (for morphine N-demethylation), and in a number of cases, it has been possible to modulate the in vivo metabolism or toxicity of chemicals by deuterium substitution. A number of efforts are in progress to utilize deuterium substitution to alter the metabolism of drugs in an advantageous manner.

© 2017 Elsevier Inc. All rights reserved.

MeSH Terms (10)

Biocatalysis Cytochrome P-450 Enzyme System Deuterium Enzyme Assays Humans Hydrogen Bonding Kinetics Models, Chemical Oxidation-Reduction Substrate Specificity

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