4ysy

Crystal structure of Mitochondrial rhodoquinol-fumarate reductase from Ascaris suum with N-[(2,4-dichlorophenyl)methyl]-2-(trifluoromethyl)benzamideCrystal structure of Mitochondrial rhodoquinol-fumarate reductase from Ascaris suum with N-[(2,4-dichlorophenyl)methyl]-2-(trifluoromethyl)benzamide

Structural highlights

4ysy is a 8 chain structure with sequence from Ascaris suum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.1Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SDHA1_ASCSU Flavoprotein (Fp) subunit of the mitochondrial electron transport chain complex II which, together with the iron-sulfur protein (Ip) subunit forms the catalytic core of the complex (PubMed:12742584, PubMed:17933581, PubMed:2843227, PubMed:7739664, PubMed:7822332, PubMed:8435436). During the parasitic larvae and adult stages, which occur in an anaerobic environment, acts as a fumarate reductase by transferring electrons from rhodoquinol to fumarate (PubMed:12742584, PubMed:17933581, PubMed:2843227, PubMed:7739664, PubMed:7822332, PubMed:8435436).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 muM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 muM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.,Inaoka DK, Shiba T, Sato D, Balogun EO, Sasaki T, Nagahama M, Oda M, Matsuoka S, Ohmori J, Honma T, Inoue M, Kita K, Harada S Int J Mol Sci. 2015 Jul 7;16(7):15287-308. doi: 10.3390/ijms160715287. PMID:26198225^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Amino H, Osanai A, Miyadera H, Shinjyo N, Tomitsuka E, Taka H, Mineki R, Murayama K, Takamiya S, Aoki T, Miyoshi H, Sakamoto K, Kojima S, Kita K. 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. Mol Biochem Parasitol. 2003 May;128(2):175-86. PMID:12742584 doi:10.1016/s0166-6851(03)00074-4
↑ Iwata F, Shinjyo N, Amino H, Sakamoto K, Islam MK, Tsuji N, Kita K. Change of subunit composition of mitochondrial complex II (succinate-ubiquinone reductase/quinol-fumarate reductase) in Ascaris suum during the migration in the experimental host. Parasitol Int. 2008 Mar;57(1):54-61. PMID:17933581 doi:10.1016/j.parint.2007.08.002
↑ Kita K, Takamiya S, Furushima R, Ma YC, Suzuki H, Ozawa T, Oya H. Electron-transfer complexes of Ascaris suum muscle mitochondria. III. Composition and fumarate reductase activity of complex II. Biochim Biophys Acta. 1988 Sep 14;935(2):130-40. PMID:2843227 doi:10.1016/0005-2728(88)90210-1
↑ Kuramochi T, Hirawake H, Kojima S, Takamiya S, Furushima R, Aoki T, Komuniecki R, Kita K. Sequence comparison between the flavoprotein subunit of the fumarate reductase (complex II) of the anaerobic parasitic nematode, Ascaris suum and the succinate dehydrogenase of the aerobic, free-living nematode, Caenorhabditis elegans. Mol Biochem Parasitol. 1994 Dec;68(2):177-87. PMID:7739664 doi:10.1016/0166-6851(94)90163-5
↑ Saruta F, Kuramochi T, Nakamura K, Takamiya S, Yu Y, Aoki T, Sekimizu K, Kojima S, Kita K. Stage-specific isoforms of complex II (succinate-ubiquinone oxidoreductase) in mitochondria from the parasitic nematode, Ascaris suum. J Biol Chem. 1995 Jan 13;270(2):928-32. PMID:7822332 doi:10.1074/jbc.270.2.928
↑ Takamiya S, Kita K, Wang H, Weinstein PP, Hiraishi A, Oya H, Aoki T. Developmental changes in the respiratory chain of Ascaris mitochondria. Biochim Biophys Acta. 1993 Feb 8;1141(1):65-74. PMID:8435436 doi:10.1016/0005-2728(93)90190-q
↑ Inaoka DK, Shiba T, Sato D, Balogun EO, Sasaki T, Nagahama M, Oda M, Matsuoka S, Ohmori J, Honma T, Inoue M, Kita K, Harada S. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria. Int J Mol Sci. 2015 Jul 7;16(7):15287-308. doi: 10.3390/ijms160715287. PMID:26198225 doi:http://dx.doi.org/10.3390/ijms160715287

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OCA

[1] Amino H, Osanai A, Miyadera H, Shinjyo N, Tomitsuka E, Taka H, Mineki R, Murayama K, Takamiya S, Aoki T, Miyoshi H, Sakamoto K, Kojima S, Kita K. 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. Mol Biochem Parasitol. 2003 May;128(2):175-86. PMID:12742584 doi:10.1016/s0166-6851(03)00074-4

[2] Iwata F, Shinjyo N, Amino H, Sakamoto K, Islam MK, Tsuji N, Kita K. Change of subunit composition of mitochondrial complex II (succinate-ubiquinone reductase/quinol-fumarate reductase) in Ascaris suum during the migration in the experimental host. Parasitol Int. 2008 Mar;57(1):54-61. PMID:17933581 doi:10.1016/j.parint.2007.08.002

[3] Kita K, Takamiya S, Furushima R, Ma YC, Suzuki H, Ozawa T, Oya H. Electron-transfer complexes of Ascaris suum muscle mitochondria. III. Composition and fumarate reductase activity of complex II. Biochim Biophys Acta. 1988 Sep 14;935(2):130-40. PMID:2843227 doi:10.1016/0005-2728(88)90210-1

[4] Kuramochi T, Hirawake H, Kojima S, Takamiya S, Furushima R, Aoki T, Komuniecki R, Kita K. Sequence comparison between the flavoprotein subunit of the fumarate reductase (complex II) of the anaerobic parasitic nematode, Ascaris suum and the succinate dehydrogenase of the aerobic, free-living nematode, Caenorhabditis elegans. Mol Biochem Parasitol. 1994 Dec;68(2):177-87. PMID:7739664 doi:10.1016/0166-6851(94)90163-5

[5] Saruta F, Kuramochi T, Nakamura K, Takamiya S, Yu Y, Aoki T, Sekimizu K, Kojima S, Kita K. Stage-specific isoforms of complex II (succinate-ubiquinone oxidoreductase) in mitochondria from the parasitic nematode, Ascaris suum. J Biol Chem. 1995 Jan 13;270(2):928-32. PMID:7822332 doi:10.1074/jbc.270.2.928

[6] Takamiya S, Kita K, Wang H, Weinstein PP, Hiraishi A, Oya H, Aoki T. Developmental changes in the respiratory chain of Ascaris mitochondria. Biochim Biophys Acta. 1993 Feb 8;1141(1):65-74. PMID:8435436 doi:10.1016/0005-2728(93)90190-q

[7] Inaoka DK, Shiba T, Sato D, Balogun EO, Sasaki T, Nagahama M, Oda M, Matsuoka S, Ohmori J, Honma T, Inoue M, Kita K, Harada S. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria. Int J Mol Sci. 2015 Jul 7;16(7):15287-308. doi: 10.3390/ijms160715287. PMID:26198225 doi:http://dx.doi.org/10.3390/ijms160715287

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