INHIBITORS OF DE NOVO PURINE BIOSYNTHESIS IN FUNGI

嘌呤从头生物合成是一个主要的代谢过程， 在脊椎动物和真菌中发现不同。关键步骤包括 AIR（5-氨基咪唑核糖核苷酸）羧化为CAIR，4- 羧基-5-氨基咪唑核苷酸。在真菌系统中， 酶，PurK和PurE，需要产生CAIR，而脊椎动物 系统只需要空气羧化酶。更重要的是，真菌途径 通过一个短暂的中间体N/5-cair（5- 羧基氨基咪唑核糖核苷酸），在CAIR的形成。基于 这些酶反应性的显著差异，可能是可行的， 合成一种能选择性作用于真菌酶的抑制剂。 本研究培训提案的目标是设计一个图书馆， 潜在的抑制剂的真菌酶，PurK和PurE，由固体- 支持化学使用组合化学的变化称为 阵列化学平行阵列将由36种化合物组成 同时合成，但分开。合成的化合物 该阵列是5-氨基吡唑核糖核苷酸（APR）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实验中进行测试。 酶和抗真菌筛选。

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.