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Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS.

ABSTRACT: Protein farnesyltransferase (FTase) catalyzes farnesylation of a variety of peptide substrates. (3)H ?-secondary kinetic isotope effect (?-SKIE) measurements of two peptide substrates, CVIM and CVLS, are significantly different and have been proposed to reflect a rate-limiting S(N)2-like transition state with dissociative characteristics for CVIM, while, due to the absence of an isotope effect, CVLS was proposed to have a rate-limiting peptide conformational change. Potential of mean force quantum mechanical/molecular mechanical studies coupled with umbrella sampling techniques were performed to further probe this mechanistic dichotomy. We observe the experimentally proposed transition state (TS) for CVIM but find that CVLS has a symmetric S(N)2 TS, which is also consistent with the absence of a (3)H ?-SKIE. These calculations demonstrate facile substrate-dependent alterations in the transition state structure catalyzed by FTase.

SUBMITTER: Yang Y

PROVIDER: S-EPMC3277741 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS.

Yang Yue Y Wang Bing B Ucisik Melek N MN Cui Guanglei G Fierke Carol A CA Merz Kenneth M KM

Journal of the American Chemical Society 20120106 2

Protein farnesyltransferase (FTase) catalyzes farnesylation of a variety of peptide substrates. (3)H α-secondary kinetic isotope effect (α-SKIE) measurements of two peptide substrates, CVIM and CVLS, are significantly different and have been proposed to reflect a rate-limiting S(N)2-like transition state with dissociative characteristics for CVIM, while, due to the absence of an isotope effect, CVLS was proposed to have a rate-limiting peptide conformational change. Potential of mean force quant ...[more]

PMID: 22206225

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Dataset Information

Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS.

Publications

Insights into the mechanistic dichotomy of the protein farnesyltransferase peptide substrates CVIM and CVLS.

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