Work

Towards rational drug design: crystal structures of glycinamide ribonucleotide transformylase

Year: 1996

Type: article

Abstract: Enzymes involved in pmine or pyiimidine biosynthesis are potential targets for the treatment of degenerative diseases of the replication cycle.Glycinamicle ribonucleotide transformylase (GAR Tfase) catalyses the first of two steps in de novo pmine biosynthesis that require reduced folate cofactors.The enzyme catalyses the transfer of a formyl group from 10formyltetrahydrofolate (l O-CHOH4F) to the amino group of glycinamide ribonucleotide (GAR) to form formyl glycinamicle Iibonucleoticle (FGAR) and tetrahydrofolate (H4F).The discovery that inhibitors of GAR-Tfase, derivatives of 5, l 0dideazatetrahydrofolate, 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), clehyclrofolate reductase (DHFR) and ribonucleotide reductase.Therefore.the focus of our studies have been to investigate the crystal stmctures of both wild type (1.2) and mutant forms of GARTfase in complex with several substrate cofactors and inhibitors to delineate.design and test new drug lead compounds of this enzyme.

Source: Acta Crystallographica Section A Foundations of Crystallography

DOI: 10.1107/s0108767396091209