Transition state analysis of the chemical and enzymatic prenylation reactions

MEDI 19

Mark D. Distefano, diste001@umn.edu, Departments of Chemistry and Medicinal Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, Stepan Lenevich, lenev001@umn.edu, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, and Christopher J Cramer, cramer@pollux.chem.umn.edu, Department of Chemistry and Supercomputing Institute, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455-0431.
Protein prenylation involves the attachment of C15 (farnesyl) or C20 (geranylgeranyl) groups to proteins and is catalyzed by a class of enzymes known as prenyltransferases. The observation that inhibition of Ras farnesylation arrests the growth of tumor cells has been the motivating factor in developing inhibitors of prenyltransferases that can serve as anticancer drugs; currently several candidates are in Phase 3 clinical trials. We are interested in using kinetic isotope effect (KIE) measurements to determine the transition state (TS) structure for the enzyme catalyzed reaction since knowledge of the TS structure may allow the selectivity and affinity of inhibitors of these enzymes to be improved. Here, using a primary 13C KIE and a secondary 2H KIE measured via mass spectrometry, a TS structure for the protein farnesyltransferase enzyme catalyzed reaction was computed; a density functional level of electronic structure theory using the mPW1N functional in combination with the 6-31+G(d) basis set was employed for those calculations. The results indicate that the enzyme effects catalysis via an “exploded” TS structure.
 

General Oral Session
1:30 PM-4:50 PM, Sunday, August 19, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007