| Project/Area Number |
13854011
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
寄生虫学(含医用動物学)
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KITA Kiyoshi The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (90134444)
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| Co-Investigator(Kenkyū-buntansha) |
HARADA Shigeharu Kyoto Institute of Technology, Department of Applied Biology, Professor, 繊維学部, 教授 (80156504)
MIYOSHI Hideto Kyoto University, Graduate School of Agriculture, Associate Professor, 大学院・農学研究科, 助教授 (20190829)
WATANABE Yohichi The University of Tokyo, Graduate School of Medicine, Lecturer, 大学院・医学系研究科, 講師 (90323568)
AMINO Hisako The University of Tokyo, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (10323601)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥98,280,000 (Direct Cost: ¥75,600,000、Indirect Cost: ¥22,680,000)
Fiscal Year 2004: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2003: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2002: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2001: ¥48,880,000 (Direct Cost: ¥37,600,000、Indirect Cost: ¥11,280,000)
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| Keywords | mitochondria / complex II / NADH-fumarate reductase / Ascaris suum / parasite / crystal structure analysis / adaptation to low oxygen tension / biosynthesis of ubiquinone / NADH-フアル酸還元系 / HIF-1 / 呼吸鎖 / フマル酸還元酵素 / ロドキノン |
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| Research Abstract |
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.
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