Fatty Acid Biosynthesis in Cryptosporidium parvum

隐孢子虫是一种单细胞病原体，可引起人类严重的水样腹泻， 动物这种病原体可以引起艾滋病患者的机会性感染， 目前仍有有效的治疗方法。隐孢子虫也是一种重要的水和食物传播的病原体， 并被列为美国国立卫生研究院生物防御研究计划中的B类优先病原体之一。缓慢 抗隐孢子虫病化学疗法的发展主要是由于对隐孢子虫病的基础 这种寄生虫的代谢途径。许多明确定义或有前途的药物靶点在其他药物中发现， 在C.小的因此，详细的分子和 功能研究表明，C.需要通过微小的代谢途径来理解 控制这种寄生虫。 脂肪酸是所有细胞的基本成分之一。我们率先研究了 酸合成C.小的我们目前的数据表明，C。与其他植物不同， 缺乏II型FAS及其相关的顶质体，依赖于三种不同的途径， 用于延长脂肪酸（即，I型模块脂肪酸合酶（CpFASI），聚酮合酶， （CpPKSI）和长链脂肪酰基延长酶（CpLCE 1）。此外，我们已经确定了假定的主要 组成的高度流线型的脂肪酸代谢的小隐孢子虫。现在这些进步 让我们能够理性地剖析C的功能。脂肪酸代谢的详细研究。 我们的长期目标是描述构成脂肪酸的主要成分的功能 C. parvum和探索这一途径作为一个合理的药物靶点。我们的假设是少校 参与C.脂肪酸代谢与人类的相应物不同， 动物在结构和功能水平，并可能作为合理的药物靶点。在本提案中，我们 将集中研究不同的机制，管理脂肪酸延长和激活在C。parvum by 实现了以下三个具体目标：1）描绘控制脂肪代谢的分子机制 通过CpFASI，CpPKS！和膜相关脂肪 酸性延伸酶2)为了阐明脂肪酸的活化和转运的分子机制， 通过对酰基辅酶A脱氢酶和脂肪酰基辅酶A结合蛋白的功能分析，3)以验证 脂肪酸代谢酶可能通过发现抑制剂而成为合理的药物靶点 选择性地对抗寄生虫脂肪酸代谢酶。

Cryptosporidium parvum is a unicellular pathogen that can cause severe watery diarrhea in humans and animals. This pathogen can cause one of the opportunistic infections in AIDS patients for which no complete effective treatment is yet available. Cryptosporidium is also a significant water- and food-borne pathogen, and listed as one of the Category B priority pathogens in the NIH biodefense research program. The slow development of anti-cryptosporidiosis chemotherapy is primarily due to the poor understanding on the basic metabolic pathways in this parasite. Many well-defined or promising drug targets found in other apicomplexans are either absent or highly divergent in C. parvum. Therefore, detailed molecular and functional studies on the unique C. parvum metabolic pathways are needed for the understanding and control of this parasite. Fatty acids are one of the essential components in all cells. We have pioneered the research on the fatty acid synthesis in C. parvum. Our current data have revealed that C. parvum differs from other apicomplexans by lacking Type II FAS and its associated apicoplast, and relying on three distinct pathway for elongating fatty acids (ie. a Type I modular fatty acid synthase (CpFASI), a polyketide synthase (CpPKSI), and a long chain fatty acyl elongase (CpLCEl). In addition, we have identified putative major components that constitute the highly streamlined fatty acid metabolism in C.parvum. These advances now allow us to rationally dissect the function of C. parvum fatty acid metabolism in detail. Our long-term goal is to delineate the function(s) of major components constituting the fatty acid metabolism in C. parvum and to explore this pathway as a rational drug target. Our hypothesis is that major enzymes involved in the C. parvum fatty acid metabolism differ from their counterparts in humans and animals at both structural and functional levels, and may serve as rational drug targets. In this proposal, we will focus on studying different mechanisms governing fatty acid elongation and activation in C. parvum by achieving the following three specific aims: 1) To delineate the molecular machineries governing the fatty acid synthesis in the parasite by functional analyses of CpFASI, CpPKS! and a membrane-associated fatty acid elongase. 2) To elucidate the molecular mechanisms involved in the activation and transporting of fatty acids by functional analyses of acyl-CoA synthases and fatty acyl-CoA binding protein. 3) To validate that fatty acid metabolic enzymes may serve as rational drug target in Cryptosporidium by discovering inhibitors selectively against, parasite fatty acid metabolic enzymes.