CARBOCYCLIC SUBSTRATES FOR DE NOVO PURINE BIOSYNTHESIS

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This proposal describes a research effort focused on the enzymes involved in the biosynthesis of purine nucleotides and their conversion to DNA and RNA. The specific aims of this study are the synthesis and biochemical evaluation of carbocyclic analogs of the substrates of de novo purine biosynthesis and carbocyclic analogs of the products of the biosynthetic pathways for evaluation with the enzymes that reduce and polymerize the purine and pyrimidine nucleotides. The initial assessment of these analogs as substrates or inhibitors of their respective enzymes will be performed with the isolated enzymes. Should these analogs prove to be substrates for the initial enzymes of de novo purine biosynthesis, their processing through the entire pathway will 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 early enzymes and that this processing would result in the generation of an inhibitor for one or more of the enzymes which catalyze later steps of de novo synthesis or of further processing. This would provide a specific inhibitor for due novo purine biosynthesis. In addition to providing specific inhibitors for de novo purine biosynthesis, this effort will afford substrate analogs as tools for mechanistic studies of the enzymes which catalyze the biosynthesis and further processing of the purine nucleotides essential for cell growth.