CARBOCYCLIC SUBSTRATES FOR DE NOVO PURINE BIOSYNTHESIS

这份提案描述了一项专注于相关酶的研究工作。 在嘌呤核苷酸的生物合成及其转化为DNA和 核糖核酸。本研究的具体目标是合成和生化。 从头合成嘌呤底物碳环类似物的评价 生物合成产物的生物合成及其碳环类似物 用还原和聚合的酶进行评价的途径 嘌呤和嘧啶核苷酸。对这些类比的初步评估 作为它们各自酶的底物或抑制物 用分离出的酶。如果这些类似物被证明是 从头合成嘌呤的起始酶及其加工 通过整个途径将用该途径的酶进行评估 在体外重组。人们希望其中的一些类比将是 被接受为早期酶的底物，这一加工将 导致产生一种或多种酶的抑制物 其催化从头合成或进一步加工的后续步骤。 这将为适当的新的嘌呤生物合成提供一种特异的抑制物。 除了为从头开始的嘌呤提供特定的抑制剂之外 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 对细胞生长至关重要的嘌呤核苷酸的进一步加工。

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.