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）：隐孢子虫是一种单细胞病原体，可导致人类和动物的严重水性腹泻。该病原体可能引起艾滋病患者的机会性感染之一，尚无完全有效治疗。隐孢子虫也是一种重要的水和食物传播病原体，在NIH Biodefense研究计划中被列为B类优先病原体之一。抗孢子虫病化学疗法的缓慢发展主要是由于对该寄生虫基本代谢途径的理解不足。在其他Apicomplexans中发现的许多定义明确或有前途的药物靶标在C. parvum中没有或高度分歧。因此，需要了解对该寄生虫的理解和控制所需的详细的分子和功能研究。脂肪酸是所有细胞中必不可少的成分之一。我们已经开创了有关猪梭菌中脂肪酸合成的研究。 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现在，这些进步的主要成分构成了高度流线的脂肪酸代谢。白梭菌的脂肪酸代谢与在结构和功能水平上的人类和动物中的脂肪酸代谢有所不同，并且可以作为该提案中的合理药物靶标。 CPFAS1，CPPKS1和膜相关脂肪酸延伸酶的分析。 2）通过对酰基-COA合酶和脂肪酰基-COA结合蛋白的功能分析来阐明与脂肪酸激活和转运有关的分子机制。 3）验证脂肪酸代谢酶可以通过选择性地发现抑制剂对寄生虫脂肪酸代谢酶的抑制剂来作为隐孢子虫中的合理药物靶标。