Evaluation of the transition state structure of the enzymatic farnesylation reaction

ORGN 87

Stepan Lenevich, lenev001@umn.edu, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455 and Mark D. Distefano, diste001@umn.edu, Departments of Chemistry and Medicinal Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455.
Protein farnesyltransferase (PFTase) catalyzes farnesyl moiety attachment to cysteine in some proteins. Since Ras proteins require farnesylation of a cysteine group to function, PFTase inhibitors can be used as anticancer therapeutics. Transition state (TS) analogs can form the tightest complex with PFTase, and could be the optimal candidates for anticancer drugs development.

We are employing kinetic isotope effect (KIE) measurements to evaluate the mechanism and the structure of the TS in the enzymatic farnesylation reaction. The KIEs in the yPFTase catalyzed geranylation of a peptide were measured by integration of the mass spectra of isotopically enriched material. The TS structure was optimized using Gaussian, the key bond lengths were adjusted, and the KIEs for new structures were calculated. The structure with calculated KIEs closest to the experimentally measured values describes the transition state in the enzymatic farnesylation reaction. This approach provides insights for anticancer drug design that target protein prenylation.

 

Process R&D, Physical Organic Chemistry, Heterocycles, Aromatics, Metal-Mediated Reactions
8:00 PM-10:00 PM, Sunday, March 25, 2007 Hyatt Regency Chicago -- Riverside Center, Poster

Division of Organic Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007