BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES

疟疾寄生虫中的生物能量学和质子泵

基本信息

批准号：
7163702
负责人：
AKHIL B VAIDYA
金额：
$ 32万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163702
关键词：
ATP Hydrolysis Acids Affect Animals Area Bacteria Biochemical Biochemistry Bioenergetics Cell membrane Cell physiology Cells Cellular biology Characteristics Charge Chemicals Cities Complex Cytoplasm Data Diphosphates Disruption Doctor of Philosophy Economics Endosome Proton Energy-Generating Resources Environment Enzymes Equilibrium Erythrocytes Face Gatekeeping Genes Glucose Glycolysis Goals Hand Homeostasis Homologous Gene Human Resources Hydrolysis Immunology Instruction Investigation Ions Knowledge Lead Location Lysosome Proton Maintenance Malaria Medicine Membrane Metabolic Microbiology Mitochondria Multienzyme Complexes Na(+)-K(+)-Exchanging ATPase Names Numbers Object Attachment Parasites Pathway interactions Philadelphia Phosphorylation Physiology Plants Plasmodium Poison Principal Investigator Printing Property Proteins Proton Pump Proton-Motive Force Proton-Translocating ATPases Protons Pump Reaction Research Personnel Research Project Grants Role Staging Surface System Thermodynamics Transport Process Universities Work Yeasts base college inhibitor/antagonist member novel strategies parasite genome plant fungi programs protein protein interaction pyrophosphatase vacuolar H+-ATPase yeast two hybrid system

项目摘要

Transport across the plasma membrane is a critical feature of all cellular physiology. Many gatekeepers at the plasma membrane are assisted by ionic and electric gradients across the membrane. Cells expend enormous energy-- up to 50% of intracellular ATP-- for maintenance of such electrochemical gradients. Energy economics of charging the plasma membrane with an electrochemical gradient for such transport remains virtually unknown in malaria parasites. The fact that erythrocytic stages of malaria parasites derive their ATP mainly through substrate-level phosphorylation, eking out a mere two ATP molecules per glucose molecule, must place significant constraints on parasite energy utilization. This project seeks to explore an alternate and/or adjunct energy source for malaria parasites. Recent evidence shows that Plasmodium species contains two members (PfVP1 and PfVP2) of the plant-like energy- conserving, membrane-associated H*-pumping pyrophosphatases. The vacuolar pyrophosphatases (V-PPases) of plants couple the energy generated by hydrolysis of the phosphoanhydride bond of inorganic pyrophosphate (PP_) to pump H ? across the vacuolar membrane. In malaria parasites, preliminary data suggest that the enzyme is located within the parasite plasma membrane. This location would suggest that H? translocation across the parasite plasma membrane could be energized through PP_ hydrolysis by the PPases in concert with ATP hydrolysis by the V-type ATPase. Because animal cells do not possess homologues of V-PPases, the presence of these enzymes in malaria parasites offers candidates for devising selectively toxic inhibitors. This project will undertake basic investigations on the biochemistry and cell biology of PfVP1 and PfVP2. Gene disruption approaches will be undertaken to assess contributions made by these molecules to the parasite physiology. The possibility that V-ATPase of malaria parasites may function work in reverse to synthesize ATP by using the proton motive force generated by the V-PPases under high energy demand will be explored. Furthermore, an unusual subunit configuration observed for the FoF1-ATP synthase of malaria parasites will be investigated to assess the contribution of this usually mitochondrial proton pumping complex to parasite physiology. Results from this project have a potential to require a major revision of our view of malaria parasite bioenergetics. Unique features of proton homeostasis and bioenergetics in malaria parasites likely to be uncovered in this project could form the basis for devising novel approaches to malaria control

跨质膜的转运是所有细胞生理学的关键特征。等离子体的许多守门人膜在整个膜上的离子和电梯度的辅助。细胞消耗巨大的能量 - 直到细胞内ATP的50％ - 用于维持此类电化学梯度。充电的能源经济学具有这种运输的电化学梯度的质膜在疟疾寄生虫中几乎是未知的。疟疾寄生虫的红细胞阶段主要通过底物级磷酸化得出其ATP，每个葡萄糖分子仅一个两个ATP分子，必须对寄生虫的能量产生重大约束利用率。该项目旨在探索疟疾寄生虫的替代和/或辅助能源。最近的有证据表明，疟原虫包含植物样能量的两个成员（PFVP1和PFVP2）保存，膜相关的H* - 泵送的焦磷酸酶。液泡焦磷酸酶（V-PPases）植物将无机焦磷酸（PP_）磷酸甘油氢键的水解产生的能量融为一体泵H？穿过液泡膜。在疟疾寄生虫中，初步数据表明该酶位于在寄生虫质膜内。这个位置会暗示H吗？寄生虫等离子体的易位膜可以通过PP_通过PPases与V型ATP水解一起通过PP_的水解来通电 ATPase。由于动物细胞不具有V-PPases的同源物，因此这些酶在疟疾中的存在寄生虫提供候选有选择性毒性抑制剂的候选者。该项目将对 PFVP1和PFVP2的生物化学和细胞生物学。将采取基因破坏方法来评估这些分子对寄生虫生理的贡献。疟疾寄生虫的V-ATPase的可能性可以通过使用V-PPases产生的质子动力力反向合成ATP的功能起作用将探索高能源需求。此外，观察到FOF1-ATP的异常亚基配置将研究疟疾寄生虫合成酶，以评估该通常线粒体质子的贡献泵送复合物到寄生虫生理。该项目的结果有可能需要对我们的重大修订疟疾寄生虫生物能学的视图。质子稳态和生物能力的独特特征在疟疾寄生虫中在这个项目中可能会发现的可能是设计新颖的疟疾控制方法的基础