TOWARDS RATIONAL DRUG DESIGN: CRYSTAL STRUCTURES OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE. Samantha E. Greasley1, Vicente Reyes1, Enrico A. Stura1, Mark S. Warren2, Stephen J. Benkovic2, Nancy E. Haynes1, D. Boger1 and Ian A. Wilson1. 1Departments of Molecular Biology and Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Rd, La Jolla, CA 92037. 2Department of Chemistry, Pennsylvania State University, University Park, PA 16802.
Enzymes involved in purine or pyrimidine biosynthesis are potential targets for the treatment of degenerative diseases of the replication cycle. Glycinamide ribonucleotide transformylase (GAR Tfase) catalyses the first of two steps in de novo purine biosynthesis that require reduced folate cofactors. The enzyme catalyses the transfer of a formyl group from 10- formyltetrahydrofolate (10-CHOH4F) to the amino group of glycinamide ribonucleotide (GAR) to form formyl glycinamide ribonucleotide (FGAR) and tetrahydrofolate (H4F). The discovery that inhibitors of GAR-Tfase, derivatives of 5,10-dideazatetrahydrofolate, are able to stop proliferation of tumor cells in culture suggested this enzyme as a target for antineoplastic agents. Structure-based rational drug design has proven useful in the development of inhibitors for enzymes such as thymidylate synthase (TS), dehydrofolate reductase (DHFR) and ribonucleotide reductase. Therefore, the focus of our studies have been to investigate the crystal structures of both wild type (1,2) and mutant forms of GAR-Tfase in complex with several substrate cofactors and inhibitors to delineate, design and test new drug lead compounds of this enzyme.
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