Kita Kiyoshi, Nihei Coichi, Tomitsuka Eriko
Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Curr Med Chem. 2003 Dec;10(23):2535-48. doi: 10.2174/0929867033456549.
Parasites have developed a wide variety of physiological functions to survive within the specialized environments of the host. Regarding energy metabolism, which represents an essential factor for survival, parasites adapt low oxygen tension in host mammals using metabolic systems that differ substantially from those of the host. Most parasites do not use free oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. Furthermore, parasites display marked changes in mitochondrial morphology and components during the life cycle, and these represent very interesting elements of biological processes such as developmental control and environmental adaptation. The enzymes in parasite-specific pathways offer potential targets for chemotherapy. Cyanide-insensitive trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory chain of long slender bloodstream forms of the African trypanosome, which causes sleeping sickness. Recently, the most potent inhibitor of TAO to date, ascofuranone, was isolated from the phytopathogenic fungus, Ascochyta visiae. The inhibitory mechanisms of ascofuranone have been revealed using recombinant enzyme. Parasite-specific respiratory systems are also found in helminths. The NADH-fumarate reductase system in mitochondria form a final step in the phosphoenolpyruvate carboxykinase (PEPCK)-succinate pathway, which plays an important role in anaerobic energy metabolism for the Ascaris suum adult. Enzymes in this system, such as NADH-rhodoquinone reductase (complex I) and rhodoquinol-fumarate reductase (complex II), form promising targets for chemotherapy. In fact, a specific inhibitor of nematode complex I, nafuredin, has been found in mass-screening using parasite mitochondria.
寄生虫已发展出多种多样的生理功能，以便在宿主的特殊环境中生存。关于能量代谢这一生存的关键因素，寄生虫利用与宿主截然不同的代谢系统来适应宿主哺乳动物体内的低氧张力。大多数寄生虫不利用宿主体内的游离氧，而是采用氧化磷酸化以外的系统来合成ATP。此外，寄生虫在生命周期中，线粒体的形态和组成会发生显著变化，这些代表了生物过程中非常有趣的元素，如发育控制和环境适应。寄生虫特异性途径中的酶为化疗提供了潜在靶点。对氰化物不敏感的锥虫替代氧化酶（TAO）是非洲锥虫长细血流形式呼吸链的末端氧化酶，非洲锥虫会引发昏睡病。最近，从植物病原真菌葡萄座腔菌中分离出了迄今为止最有效的TAO抑制剂——阿斯科呋喃酮。已利用重组酶揭示了阿斯科呋喃酮的抑制机制。在蠕虫中也发现了寄生虫特异性的呼吸系统。线粒体中的NADH - 延胡索酸还原酶系统是磷酸烯醇丙酮酸羧激酶（PEPCK） - 琥珀酸途径的最后一步，该途径在猪蛔虫成虫的无氧能量代谢中起重要作用。该系统中的酶，如NADH - 玫红醌还原酶（复合体I）和玫红醇 - 延胡索酸还原酶（复合体II），是很有前景的化疗靶点。事实上，在利用寄生虫线粒体进行的大规模筛选中，已发现了线虫复合体I的特异性抑制剂萘呋地定。
