INHIBITORS OF DE NOVO PURINE BIOSYNTHESIS IN FUNGI

从头开始的嘌呤生物合成是一种主要的代谢过程，最近 在脊椎动物和真菌中发现不同。关键一步涉及到 空气(5-氨基咪唑核糖核苷酸)羧化为CAIR，4- 羧基-5-氨基咪唑核糖核苷酸。在真菌系统中，有两个 产生CAIR所需要的酶是Purk和Pure，而脊椎动物 系统只需要空气羧基酶。更重要的是，真菌途径 通过一个短暂的中间体N/5-CAIR(5- 羧氨基咪唑核苷酸)，在CAIR的形成中。基于 这些酶活性的显著差异，可能是可行的 合成一种能选择性作用于真菌酶的抑制剂。 这项研究培训计划的目标是设计一个 真菌酶的潜在抑制剂，Purk和Pure，通过固体- 使用组合化学的变体支持化学，称为 阵列化学。平行阵列将由36个化合物组成 同时但分开合成的。在中国合成的化合物 该阵列是5-氨基吡唑核糖核苷酸(APR)的类似物。三个领域 的多样性，以最大限度地扩大结构差异 图书馆。一旦合成，这些化合物将在几个 酵素和抗真菌筛选。

De novo purine biosynthesis, a primary metabolic process, was recently found to differ in vertebrates and fungi. The key step involves the carboxylation of AIR (5-aminoimidazole ribonucleotide) to CAIR, 4- carboxyl-5-aminoimidazole ribonucleotide. In the fungal system, two enzymes, PurK and PurE, are required to produce CAIR while the vertebrate system requires only AIR carboxylase. More importantly, the fungal pathway proceeds through a short-lived intermediate, N/5-cair (5- carboxyaminoimidazole ribonucleotide), in the formation of CAIR. Based on these significant differences in enzyme reactivity, it may be feasible to synthesize a inhibitor that would act selectively with the fungal enzymes. The goal of this research training proposal is to design a library of potential inhibitors of the fungal enzymes, PurK and PurE, by solid- supported chemistry using a variation of combinatorial chemistry called array chemistry. The parallel array will consist of 36 compounds synthesized simultaneously but separately. The compounds synthesized in the array are analogs of 5-aminopyrazole ribonucleotide (APR). Three areas of diversity have been outlined to maximize the structural differences of the library. Once synthesized, the compounds will be tested in several enzymes and anti-fungal screens.