Mechanistic and structural studies on protein prenyl transferases

V. A. Waller, T. C. Turek, I. Gaon, Mark D Distefano

Research output: Contribution to journalArticlepeer-review

Abstract

Farnesyl protein transferases (FPTase) and geranylgeranyl protein transferases (GGPTase) catalyze post-translation lipid modifications of various proteins by attaching a prenyl group from farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) to a specific cysteine residue of the protein. Currently, this is an intense area of research as a target for cancer therapy, because oncogenic Ras proteins must undergo lipid modification by a farnesyl group to be functional. We are working on increasing the understanding of these enzymes through experiments that will give information about the chemical mechanism of the prenyl transfer by FPTase and structural information about the active site of GGPTase. To understand the chemical mechanism of FPTase from yeast, we are determining the secondary kinetic isotope effect of the prenyl transfer reaction to gain information about the transition state that develops in the active site. This is being accomplished by employing the competitive label method, using enzymatically synthesized deuterated and radiolabeled FPP. For understanding the nature of the active site of recombinant human GGPTase, we are experimenting with photoaffinity labeling. We have developed a series of prenyl pyrophosphate analogs that incorporate a benzophenone group in the prenyl moiety of the compounds. Inhibition, photoinactivation, and labeling of the enzyme by these compounds will be presented. The above studies will give information that should facilitate the design of new inhibitors for both FPTase and GGPTase.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number9
StatePublished - Dec 1 1997

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