Physiological function of respiratory enzymes specific for parasite mitochondria in the adaptation to low oxygen tension

我们对寄生蠕虫A. suum呼吸链的研究表明，线粒体NA dh -富马酸还原酶系统在寄生于宿主的成虫的厌氧能量代谢中起着重要作用，并且在其生命周期中发生的发育变化中具有独特的特征。在该体系中，NADH的还原当量通过NADH-RQ还原酶复合体（复合体I）转移到低电位红醌（RQ）。这一途径最终通过复合体II的醌-富马酸还原酶活性（有氧呼吸中的琥珀酸-泛醌还原酶）产生琥珀酸。从NA DH到富马酸盐的电子转移通过产生质子动力与复合物I的I位点磷酸化耦合，质子动力足以驱动ATP合成。配合物I的动力学分析以及蠕虫配合物I同时使用rhodoquinone-9 （RQ_9）和ubiquinone-9 （UQ_9）作为电子受体的事实表明，蠕虫配合物I醌还原位点的结构特征可能与哺乳动物配合物I不同。事实上，喹唑啉类化合物对RQ_2和UQ_2的抑制机制分别为竞争和部分竞争。最近的研究表明，a . suum线粒体表达的复合体II的阶段特异性亚型：复合体II的黄蛋白亚基和细胞色素b小亚基（CybS）与成体酶不同，而两个复合体II有一个共同的铁硫簇亚基（Ip）。酶分析表明，与哺乳动物宿主的复合体II相比，成虫和幼虫的复合体II具有不同的性质，并且幼虫的复合体II能够发挥rq -富马酸还原酶的作用。在筛选A. suum复合物II抑制剂时，发现了最有效的复合物II抑制剂Atpenin A5。我们获得了线粒体rq -富马酸还原酶第一个例子的成人复合体II晶体。

Our studies on respiratory chain of the parasitic helminth, A. suum, has shown that the mitochondrial NA DH-fumarate reductase system plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts as well as unique features of the developmental changes that occur during their life cycle. In this system, the reducing equivalent of NA DH is transferred to the low-potential rhodoquinone (RQ) by the NADH-RQ reductase complex (Complex I). This pathway ends with the production of succinate by the quinol-fumarate reductase activity of complex II (succinate-ubiquinone reductase in aerobic respiration). Electron transfer from NA DH to fumarate is coupled to site I phosphorylation of complex I via generation of a proton motive force, which is sufficiently high to drive ATP synthesis.Kinetic analysis of Complex I along with the fact that helminth complex I uses both rhodoquinone-9 (RQ_9) and ubiquinone-9 (UQ_9) as an electron acceptor suggest that the structural features of the quinone reduction site of helminth complex I may differ from that of mammalian complex I. In fact, the inhibitory mechanism of quinazolines was competitive and partially competitive against RQ_2 and UQ_2, respectively.Recently study showed that A. suum mitochondria express stage-specific isoforms of complex II: the flavoprotein subunit and the small subunit of cytochrome b (CybS) of the larval complex II differ from those of adult enzyme, while two complex II's share a common iron-sulfur cluster subunit (Ip). Enzymatic assays revealed that the adult and larval A. suum complex II's have different properties than the complex II of the mammalian host and that the larval complex II is able to function as a RQ-fumarate reductase. Most potent inhibitor of complex II, Atpenin A5 was found during the screening of inhibitors for A. suum complex II. We obtained a crystal of adult complex II for the first example of mitochondrial RQ-fumarate reductase.