CARBOCYCLIC SUBSTRATES FOR DE NOVO PURINE BIOSYNTHESIS

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This proposal describes a research effort focused in the enzymes which catalyze the initial steps of de novo purine biosynthesis. The specific aims of this study are the synthesis and testing of carbocyclic nucleotide substrate analogs for the first several enzymes of the pathway, namely glycinamide ribonucleotide synthetase, glycinamide ribonucleotide transformylase, formyl glycinamidine ribonucleotide synthetase and aminoimidazole ribonucleotide synthetase. The initial assessment of these analogs as substrates or inhibitors of the respective enzymes will be performed with the purified enzymes. Should these analogs prove to bs substrates of these initial enzymes, there processing through the entire pathway would be assessed with the enzymes of the pathway reconstituted in vitro. It is hoped that some of the analogs will be accepted as substrates for the enzymes which catalyze the initial steps in the pathway and that this processing would result in the generation of an inhibitor for one or more of the enzymes which catalyzes later steps. This would provide a specific inhibitor for de novo purine biosynthesis, which has recently been demonstrated to be an important metabolic target for cancer chemotherapy. In addition to providing specific inhibitors of de novo purine biosynthesis, this effort will afford substrate analogs as tools for mechanistic studies in the enzymes which catalyze the initial steps in this metabolically important biosynthetic pathway.