Fatty Acid Biosynthesis in Cryptosporidium parvum

微小隐孢子虫是一种单细胞病原体，可导致人类严重水样腹泻和 动物。这种病原体可以引起艾滋病患者的一种机会性感染，对这种感染没有完全 目前还没有有效的治疗方法。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NIH生物防御研究计划的B类优先病原体之一。慢的 抗隐孢子虫病化疗的发展主要是由于对基础知识的认识不足。 这种寄生虫的代谢途径。许多明确的或有希望的药物靶点在其他 尖端复合体不是缺失就是高度分化。因此，详细的分子和 需要对微小隐孢子虫独特的代谢途径进行功能研究，以了解和 控制住这种寄生虫。 脂肪酸是所有细胞的基本成分之一。我们开创了肥胖症研究的先河 微小隐孢子虫的酸合成。我们目前的数据显示，微小隐孢子虫不同于其他 缺乏II型Fas及其相关的顶体复合体，依赖于三条不同的途径 用于延长脂肪酸(即I型模块化脂肪酸合成酶(CpFASI)，一种聚酮合成酶 (CpPKSI)和一个长链脂肪酰基延长酶(CpLCEl)。此外，我们已经确定了可能的少校 组成微小隐孢子虫高度流线型脂肪酸代谢的成分。现在的这些进步 让我们理性地剖析微小隐翅虫脂肪酸代谢的功能。 我们的长期目标是描绘出组成脂肪酸的主要成分的功能(S) 探讨这一途径作为合理的药物靶点。我们的假设是 参与微小隐孢子虫脂肪酸代谢的酶不同于人类和 动物在结构和功能水平上，并可能作为合理的药物靶点。在这项提案中，我们 将重点研究不同的机制控制脂肪酸拉长和激活微小隐孢子虫 实现以下三个具体目标：1)描述控制脂肪的分子机制 利用CpFASI、CpPKS！和一种膜相关脂肪 酸性伸长酶。2)阐明脂肪活化和转运的分子机制 酰辅酶A合成酶和脂肪酰辅酶A结合蛋白的功能分析。3)验证这一点 通过发现抑制物，脂肪酸代谢酶可能成为隐孢子虫的合理药物靶点 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.