| アイテムタイプ |
学術雑誌論文 / Journal Article(1) |
| 公開日 |
2026-02-03 |
| タイトル |
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タイトル |
Modulation of succinyl‐CoA:3‐ketoacid CoA transferase activity by a single amino acid residue in acetate:succinate CoA transferase from Trypanosoma brucei, the causative agent of African sleeping sickness |
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言語 |
en |
| 言語 |
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言語 |
eng |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
acetate metabolism |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
|
主題 |
acetate: Succinate CoA-transferase |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
crystal structure |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
energy metabolism |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
human African trypanosomiasis |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
mitochondria |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
site-directed mutagenesis |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
substrate bindingsites |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
substrate specificity |
| キーワード |
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言語 |
en |
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主題Scheme |
Other |
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主題 |
succinyl-CoA:3-ketoacid CoA transferase |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 著者 |
Mochizuki, Kota
Inaoka, Daniel Ken
Fukuda, Keisuke
Kurasawa, Hana
Iyoda, Kenji
Nakai, Uta
Harada, Shigeharu
Balogun, Emmanuel O.
Bringaud, Frédéric
Boshart, Michael
Sakura, Takaya
Hirayama, Kenji
Kita, Kiyoshi
Shiba, Tomoo
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| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
Trypanosomatids are protozoan parasites that remain a global health challenge due to the limited efficacy, safety, and durability of current treatments. Acetate: succinate CoA transferase (ASCT), together with succinyl-CoA synthase (SCS), forms the ASCT/SCS cycle that fuels ATP production and generates acetate, a central metabolic intermediate essential for mitochondrial pathways in these parasites. Although Trypanosoma brucei ASCT (TbASCT) shares 52% amino acid identity with mammalian succinyl-CoA:3-ketoacid CoA transferase (mSCOT), the latter catalyzes a rate-limiting step of ketone body catabolism. Because ASCT and SCOT perform distinct reactions, understanding their mechanistic divergence is crucial for identifying parasite-specific vulnerabilities and advancing selective drug discovery. Here, we report crystal structures of TbASCT bound to all substrates and products, revealing the molecular basis of substrate recognition and catalysis. In solution, TbASCT and mSCOT are homotetrameric and homodimeric, respectively. Despite similar monomer fold, the substrate-binding sites and catalytic mechanisms by which these two enzymes mediate different reactions remain unknown. Site-directed mutagenesis demonstrated that residues Arg162, Leu377, and Asp62 govern tetramer assembly, CoA binding, and acquisition of SCOT activity, respectively. Mutation of Leu377 abolished ASCT activity, while Arg162 mutant produced ASCT-active dimers with a 10-fold increase in SCOT/ASCT activity ratio. Notably, Asp62 mutants exhibited more than 4000-fold increase in this ratio, representing gain-of-function SCOT activity, a reaction absent in TbASCT. These mechanistic insights define the structural determinants that separate ASCT from SCOT function and illuminate opportunities to selectively inhibit ASCT without disrupting host SCOT, thereby informing the development of trypanosomatid-targeted therapeutics. |
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言語 |
en |
| 書誌情報 |
en : Protein Science
巻 35,
号 2,
p. art. no. e70463,
発行日 2026-01-20
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| 出版者 |
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出版者 |
John Wiley and Sons Inc |
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言語 |
en |
| ISSN |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
0961-8368 |
| DOI |
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関連タイプ |
isIdenticalTo |
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識別子タイプ |
DOI |
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関連識別子 |
https://doi.org/10.1002/pro.70463 |
| 権利 |
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|
権利情報 |
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. |
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言語 |
en |
| 著者版フラグ |
|
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出版タイプ |
VoR |
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出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| 引用 |
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内容記述タイプ |
Other |
|
内容記述 |
Protein Science, 35(2), art. no. e70463; 2026 |
|
言語 |
en |
PS35_e70463.pdf (3.3 MB)
