Fatty Acid Biosynthesis in Cryptosporidium parvum

小隐孢子虫中的脂肪酸生物合成

• 批准号: 7191624
• 负责人: GUAN ZHU
• 金额: $ 31.79万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191624
• 关键词: Acetyl-CoA Carboxylase; Acids; Acquired Immunodeficiency Syndrome; Acyl Carrier Protein; Acyl Coenzyme A; Animals; Antibiotics; Bacteria; Biochemical; Bioinformatics; Boxing; Carbon; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chimeric Proteins; Chlorine; Coccidia; Coenzyme A; Communities; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Data; Development; Diarrhea; Diazepam Binding Inhibitor; Drug Delivery Systems; Eimeria; Electrons; Enzymes; Essential Fatty Acids; Fatty Acids; Fatty-acid synthase; Figs - dietary; Fluorescence Resonance Energy Transfer; Genomics; Goals; Hand; Human; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Intestines; Life; Lipids; Malonyl Coenzyme A; Medium chain fatty acid; Membrane; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mono-S; Morbidity - disease rate; Murine pneumonia virus; Numbers; Oocysts; Opportunistic Infections; Organism; Oxidoreductase; Parasite Control; Parasites; Pathway interactions; Patients; Pharmaceutical Preparations; Plants; Plasmodium; Plastids; Polyunsaturated Fatty Acids; Process; Propionibacterium acnes; Recombinant Proteins; Research; Research Personnel; Resistance; South America; Stress; Structure; Tertiary Protein Structure; Therapeutic Corynebacterium Parvum; Toxoplasma; Transferase; United States; United States National Institutes of Health; Vacuole; Very Long Chain Fatty Acid; Vividrin akut Azelastin; Water; Water Supply; base; biodefense; chemical reaction; chemotherapy; dehydrase; enoyl reductase; fatty acid biosynthesis; fatty acid elongases; fatty acid metabolism; fatty acid synthase II; fatty acid transport; feeding; foodborne pathogen; gastrointestinal epithelium; high throughput screening; inhibitor/antagonist; long chain fatty acid; maltose-binding protein; mortality; nitazoxanide; pathogen; phosphopantetheinyl transferase; polyketide synthase; polypeptide; programs; tool

DESCRIPTION (provided by applicant): 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 (i.e. a Type I modular fatty acid synthase (CpFAS1), a polyketide synthase (CpPKS1), and a long chain fatty acyl elongase (CpLCE1). 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 CpFAS1, CpPKS1 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.

描述（由申请人提供）：小隐孢子虫是一种单细胞病原体，可引起人类和动物严重的水样腹泻。这种病原体可引起艾滋病患者的一种机会性感染，目前尚无完全有效的治疗方法。隐孢子虫也是一种重要的水源和食源性病原体，并被 NIH 生物防御研究计划列为 B 类优先病原体之一。抗隐孢子虫病化疗发展缓慢主要是由于对该寄生虫的基本代谢途径了解甚少。在其他顶复菌中发现的许多明确或有前途的药物靶点在 C. parvum 中要么不存在，要么高度不同。因此，需要对独特的 C. parvum 代谢途径进行详细的分子和功能研究，以了解和控制这种寄生虫。脂肪酸是所有细胞的必需成分之一。我们开创了小孢子虫脂肪酸合成的研究。我们目前的数据表明，C. parvum 与其他顶端复合物的不同之处在于，它缺乏 II 型 FAS 及其相关的顶端质体，并且依赖于三种不同的途径来延长脂肪酸（即 I 型模块化脂肪酸合酶 (CpFAS1)、聚酮化合物合酶 (此外，我们还确定了构成高度流线型的假定主要成分。这些进展现在使我们能够详细合理地剖析 C. parvum 脂肪酸代谢的功能，我们的长期目标是描述构成 C. parvum 脂肪酸代谢的主要成分的功能。 C. parvum 并探索该途径作为合理的药物靶标。我们的假设是，参与 C. parvum 脂肪酸代谢的主要酶在结构和功能水平上都不同于人类和动物中的对应酶，并且可以作为合理的药物。在本提案中，我们将重点研究小隐孢子虫中控制脂肪酸延伸和活化的不同机制，以实现以下三个具体目标：1）通过功能分析来描述控制寄生虫中脂肪酸合成的分子机制。 CpFAS1、CpPKS1 和膜相关脂肪酸延长酶。 2) 通过酰基辅酶A合酶和脂肪酰基辅酶A结合蛋白的功能分析，阐明脂肪酸激活和转运的分子机制。 3) 通过发现选择性针对寄生虫脂肪酸代谢酶的抑制剂，验证脂肪酸代谢酶可以作为隐孢子虫的合理药物靶点。