CARBOCYCLIC SUBSTRATES FOR DE NOVO PURINE BIOSYNTHESIS

这份提案描述了一项专注于酶的研究工作。 催化从头合成嘌呤的初始步骤。 这项研究的具体目的是综合和测试 前几种碳环核苷酸底物类似物 该途径的酶，即甘氨酰胺核糖核苷酸 合成酶，甘氨酰胺核糖核苷酸转移酶，甲酰 甘氨嘧啶核糖核苷酸合成酶和氨基咪唑 核糖核苷酸合成酶。对这些项目的初步评估 作为各自酶的底物或抑制剂的类似物 将与纯化的酶一起进行。这些应该是 类似物证明是这些最初的酶的底物。 通过整个路径的处理将使用 该途径的酶在体外重组。人们希望， 其中一些类似物将被接受为 催化该途径的初始步骤的酶，以及 该处理将导致产生一种抑制剂 用于催化后续步骤的一种或多种酶。这 会为从头开始的嘌呤提供一种特殊的抑制剂 生物合成，最近被证明是一种 癌症化疗的重要代谢靶点。此外 涉及提供从头合成的嘌呤生物合成的特异性抑制剂， 这一努力将提供底物类似物作为工具 催化起始酶的机理研究 在这一代谢重要的生物合成途径中的步骤。

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.