BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES

跨质膜运输是所有细胞生理学的重要特征。许多看门人在等离子体 跨膜的离子和电荷梯度对膜起辅助作用。细胞消耗巨大的能量--最高可达 50%的细胞内ATP--用于维持这种电化学梯度。为汽车充电的能源经济性 在疟疾寄生虫中，具有用于这种转运的电化学梯度的质膜几乎仍然未知。 事实上，疟疾寄生虫的红细胞期主要通过底物水平的磷酸化来获得它们的ATP， 每个葡萄糖分子只能勉强维持两个ATP分子，必须对寄生虫的能量施加显著的限制 利用率。该项目旨在探索疟疾寄生虫的替代和/或附属能源。近期 有证据表明，疟原虫物种含有两个类植物能量成员(PfVP1和PfVP2)。 保守的、膜相关的H~*泵焦磷酸酶。空泡焦磷酸酶(V-PPase) 植物将无机焦磷酸盐(PP_)的磷酸酸酐键水解所产生的能量耦合到 泵H？穿过液泡膜。在疟疾寄生虫中，初步数据表明这种酶位于 在寄生虫的质膜内。这个位置会表明H？在寄生虫血浆中的移位 膜可通过PPase的PP_水解酶和V-型的ATP水解酶协同作用而被激活 ATPase。因为动物细胞不具有V-PPase的同源物，所以这些酶在疟疾中的存在 寄生虫提供了设计选择性毒性抑制剂的候选药物。该项目将对以下项目进行基础调查 PfVP1和PfVP2的生物化学和细胞生物学。将采用基因破坏方法来评估 这些分子对寄生虫生理学的贡献。疟疾寄生虫V-ATPase的可能性 可能通过利用V-PPase产生的质子动力相反地合成ATP 将探索高能源需求。此外，观察到FoF1-ATP的一个不寻常的亚基配置 将对疟疾寄生虫的合成酶进行研究，以评估这种通常是线粒体质子的贡献。 泵送复合体给寄生虫生理学。此项目的结果可能需要对我们的 疟疾寄生虫生物能量学观点。疟疾寄生虫质子动态平衡和生物能量学的独特特征 可能在这个项目中被发现，可能成为设计新的疟疾控制方法的基础

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