CARBOCYCLIC SUBSTRATES FOR DE NOVO PURINE BIOSYNTHESIS

这项建议描述了一项研究工作集中在酶参与 嘌呤核苷酸的生物合成及其转化为DNA， 核糖核酸 本研究的具体目的是合成和生化 从头嘌呤底物的碳环类似物的评价 生物合成产物的碳环类似物 用还原和还原酶进行评价的途径 嘌呤和嘧啶核苷酸。 对这些类似物的初步评估 作为它们各自酶的底物或抑制剂 分离的酶。 如果这些类似物被证明是底物， 嘌呤从头生物合成的起始酶，它们的加工 将用该途径的酶来评估整个途径 在体外重组。 希望其中一些类似物能够 被接受为早期酶的底物，这种加工将 导致产生一种或多种酶的抑制剂 其催化从头合成或进一步加工的后续步骤。 这将提供一种特异性抑制剂，用于嘌呤的从头生物合成。 除了为新生嘌呤提供特异性抑制剂外， 生物合成，这一努力将提供底物类似物作为工具， 催化生物合成的酶的机理研究， 进一步加工细胞生长所必需的嘌呤核苷酸。

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.