Roles of Lipoate Pathways in Plasmodium Survival

硫辛酸途径在疟原虫存活中的作用

• 批准号: 7756575
• 负责人: Sean Taylor PRIGGE
• 金额: $ 38.66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2012-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756575
• 关键词: Abbreviations; Acyl Carrier Protein; Albumins; Antioxidants; Bacteria; Binding; Biochemical; Biological; Blood; Cell Respiration; Cells; Cellular biology; Cessation of life; Coenzyme A; Coenzymes; Communicable Diseases; Complex; Cytosol; Development; Digestion; Disease; Enzymes; Erythrocytes; Escherichia coli; Food; Genetic; Goals; Growth; Heme Iron; Hemoglobin; Housing; Human; Infection; Intestines; Iron; Ketoglutarate Dehydrogenase Complex; Life; Ligase; Lipids; Malaria; Mammalian Cell; Mammals; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular Genetics; Multienzyme Complexes; Nutrient; Organelles; Oxidoreductase; Parasites; Pathway interactions; Phosphate Buffer; Plasmodium; Plasmodium falciparum; Proteins; Pyruvate Dehydrogenase Complex; Reactive Oxygen Species; Research Personnel; Role; Saline; Serum; Serum Albumin; Staging; Stream; Therapeutic Intervention; Trichloroacetic Acid; asexual; base; cofactor; fatty acid biosynthesis; inhibitor/antagonist; lipoate; maltose-binding protein; novel therapeutic intervention; oxidative damage; prevent; programs; research study; trafficking; uptake

Malaria parasites are responsible for 300-500 million infections and 2-3 million deaths annually. During the asexual stages of development in red blood cells, parasites acquire certain nutrients from human serum while retaining the ability to synthesize others. We are studying an essential enzyme cofactor called lipoate and its metabolism in Plasmodium falciparum. Our recent studies indicate that malaria parasites contain a metabolic pathwayto synthesize lipoate de nowofrom intermediates of fatty acid biosynthesis as well as two mechanisms for scavenging lipoate from human serum. These pathways appear to reside in different subcellular compartments in the parasite and may be independent and essential for parasite survival. The proposed studies will employ biochemical, cell biology and genetic approaches to investigate these unexplored pathways and establish the roles of synthesized and host-derived lipoate in parasitesurvival. Specific Aim 1will define the activities and organization of the P. falciparum lipoate biosyntheticmachinery and the role of synthesized lipoate in parasite survival. Specific Aim 2 will define the role ofexogenous lipoate in parasite survival, its distribution in the parasite, and the activities and organization of the P. falciparum lipoate scavenging pathways. These studies could establish the existence of an intracellular metabolite trafficking pathway between the apicoplast organelle and the mitochondrion of malaria parasites. Alternatively, these studies could demonstrate that P. falciparum parasites are auxotrophic for lipoate despite the existence of a lipoate biosynthetic pathway. Proteins responsible for the metabolism of lipoate may ultimately prove to be attractive targets for therapeutic intervention - especially since inhibitors couldact synergistically with known inhibitors of P. falciparum fatty acid biosynthesis.

疟疾寄生虫每年造成3亿至5亿人感染，200万至300万人死亡。期间 在红细胞的无性发育阶段，寄生虫从人类血清中获得某些营养 同时保留合成其他的能力。我们正在研究一种叫做硫辛酸的必需酶辅因子 及其在恶性疟原虫中的代谢。我们最近的研究表明，疟疾寄生虫含有一种 从脂肪酸生物合成的中间体以及两种 从人血清中清除硫辛酸的机制。这些通路似乎位于不同的 亚细胞区室的寄生虫，并可能是独立的寄生虫生存所必需的。的 拟议中的研究将采用生物化学、细胞生物学和遗传学方法来研究这些问题。 未探索的途径，并建立合成和宿主衍生的硫辛酸在寄生虫生存中的作用。 具体目标1将定义恶性疟原虫硫辛酸生物合成机制的活动和组织 以及合成的硫辛酸在寄生虫存活中的作用。具体目标2将定义外源性 本文对硫辛酸在寄生虫体内的分布、在寄生虫体内的分布以及P. 恶性疟原虫硫辛酸清除途径。这些研究可以确定细胞内存在 疟原虫顶质体细胞器和寄生体之间的代谢物运输途径。 或者，这些研究可以证明，恶性疟原虫是营养缺陷型的硫辛酸，尽管 脂肪酸生物合成途径的存在。负责硫辛酸代谢的蛋白质可能 最终被证明是治疗干预的有吸引力的靶点-特别是因为抑制剂可以 与已知的恶性疟原虫脂肪酸生物合成抑制剂协同作用。

项目成果

Validation of a modified method for Bxb1 mycobacteriophage integrase-mediated recombination in Plasmodium falciparum by localization of the H-protein of the glycine cleavage complex to the mitochondrion.

• DOI: 10.1016/j.molbiopara.2010.04.005
• 发表时间: 2010-08
• 期刊: MOLECULAR AND BIOCHEMICAL PARASITOLOGY
• 影响因子: 1.5
• 作者: Spalding, Maroya D.;Allary, Marina;Gallagher, John R.;Prigge, Sean T.
• 通讯作者: Prigge, Sean T.

Increased prevalence of the pfdhfr/phdhps quintuple mutant and rapid emergence of pfdhps resistance mutations at codons 581 and 613 in Kisumu, Kenya.

• DOI: 10.1186/1475-2875-9-338
• 发表时间: 2010-11-24
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Spalding MD;Eyase FL;Akala HM;Bedno SA;Prigge ST;Coldren RL;Moss WJ;Waters NC
• 通讯作者: Waters NC

Plasmodium falciparum acyl carrier protein crystal structures in disulfide-linked and reduced states and their prevalence during blood stage growth.

• DOI: 10.1002/prot.22582
• 发表时间: 2010-02-15
• 期刊: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
• 影响因子: 2.9
• 作者: Gallagher, John R.;Prigge, Sean T.
• 通讯作者: Prigge, Sean T.

The amidase domain of lipoamidase specifically inactivates lipoylated proteins in vivo.

脂酰胺酶的酰胺酶结构域在体内特异性地灭活脂酰化蛋白。

• DOI: 10.1371/journal.pone.0007392
• 发表时间: 2009
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Spalding,MaroyaD;Prigge,SeanT
• 通讯作者: Prigge,SeanT

Targeting the fatty acid biosynthesis enzyme, beta-ketoacyl-acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents.

• DOI: 10.1021/jm8008103
• 发表时间: 2009-02-26
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lee PJ;Bhonsle JB;Gaona HW;Huddler DP;Heady TN;Kreishman-Deitrick M;Bhattacharjee A;McCalmont WF;Gerena L;Lopez-Sanchez M;Roncal NE;Hudson TH;Johnson JD;Prigge ST;Waters NC
• 通讯作者: Waters NC