2004 Fiscal Year Final Research Report Summary
Physiological function of respiratory enzymes specific for parasite mitochondria in the adaptation to low oxygen tension
| 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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| Keywords | mitochondria / complex II / NADH-fumarate reductase / Ascaris suum / parasite / crystal structure analysis / adaptation to low oxygen tension / biosynthesis of ubiquinone |
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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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[Journal Article] A y-Lactone Form Nafuredin, Nafuredin-y, also Inhibits Helminth Complex I2005
Author(s)
Shiomi, K., Ui, H., Suzuki, H., Hatano, H., Nagamitsu, T., Takano, D., Miyadera, H., Yamashita, T., Kita, K., Miyoshi, H., Harder, A., Tomoda, H., Omura, S.
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Journal Title
J. Antibiot. 58
Pages: 50-55
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Rhodoquinone reaction site of mitochondrial complex I, in parasitic helminth, Ascaris suum.2004
Author(s)
Yamashita, T., Ino, T., Miyoshi, H., Sakamoto K., Osanai, A., Nakamaru-Ogiso, E., Kita, K.
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Journal Title
Biochim Biophys. Acta (Bioenergetics) 1608
Pages: 97-103
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase).2003
Author(s)
Miyadera, H., Shiomi, K., Ui, H., Yamaguchi, Y., Masuma, R., Tomoda, H., Miyoshi, H., Osanai, A., Kita, K., Omura, S.
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Journal Title
Proc. Natl. Acad. Sci. USA 100
Pages: 473-477
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Purification of active recombinant Trypanosome Alternative Oxidase.2003
Author(s)
Nihei, C., Fukai, Y., Kawai, K., Osanai, A., Yabu, Y., Suzuki, T., Ohta, N., Minagawa, N., Nagai, K., Kita, K.
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Journal Title
FEBS Lett. 538
Pages: 35-40
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Complex II from Phototrophic Purple Bacterium Rhodoferax fermentans displays rhodoquinol-fumarate reductase activity.2003
Author(s)
Miyadera, H., Hiraishi, A., Miyoshi, H., Sakamoto, K., Mineki, R., Murayama, K., Nagashima' V.P., Matsuura, K., Kojima, S., Kita, K
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Journal Title
Eur. J. Biochem. 270
Pages: 1863-1874
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Complementation of Escherichia coli ubiF mutation by Caenorhabditis elegans CLK-1, a product of longevity gene of the nematode worm.2003
Author(s)
Adachi, A., Shinjyo, N., Fujita, D., Miyoshi, H., Amino, H.Watanabe, Y., Kita, K.
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Journal Title
FEBS Lett. 543
Pages: 175-179
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Isolation and characterization of the stage- specific cytochrome b small subunit (CybS) of Ascaris suum complex II from the aerobic respiratory chain of larval mitochondria.2003
Author(s)
Amino, H., Osanai, A., Miyadera, H., Shinjyo, N., Tomitsuka, T., Taka, H., Mineki, R., Murayama, K., Takamiya, S., Aoki, T., Miyoshi, H., Sakamoto, K., Kojima, S., Kita, K.
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Journal Title
Mol. Biochem. Parasitol. 128
Pages: 175-186
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase).2003
Author(s)
Tomitsuka, E., Hirawake, H., Goto, Y., Taniwaki, M., Harada, S., Kita, K.
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Journal Title
J. Biochem. 134
Pages: 191-195
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Quinones in long- lived clk-1 mutants of Caenorhabditis elegans2002
Author(s)
Miyadera, H., Kano, K., Miyoshi, H., Ishii, N., Hekimi, S., Kita, K.
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Journal Title
FEBS Lett. 512
Pages: 33-37
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Complex II inactivation is lethal in the nematode Caenorhabditis elegans2002
Author(s)
Ichimiya, H., Huet, R.G., Hartman, P., Amino, H., Kita, K., Ishii, N.
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Journal Title
Mitochondrion 2
Pages: 191-198
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans2001
Author(s)
Miyadera, H., Amino, H., Hiraishi, A., Taka, H., Murayama, M., Miyoshi, H., Sakamoto, K., Ishii, N., Hekimi, S., Kita, K.
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Journal Title
J. Biol. Chem. 276
Pages: 7713-7716
Description
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