A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1

Yasunari Sakai, Masato Furuichi, Masayuki Takahashi, Masaki Mishima, Shigenori Iwai, Masahiro Shirakawa, Yusaku Nakabeppu

研究成果: ジャーナルへの寄稿記事

61 引用 (Scopus)

抄録

MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration. This substrate specificity for oxidized purine nucleoside triphosphates was investigated by mutation analyses based on the sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-rGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, altered the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp-117 and Asp-119 of MTH1, which showed apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp-117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP, whereas Asp-119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.

元の言語英語
ページ(範囲)8579-8587
ページ数9
ジャーナルJournal of Biological Chemistry
277
発行部数10
DOI
出版物ステータス出版済み - 3 8 2002

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Substrate Specificity
Purine Nucleosides
Substrates
DNA Replication
Phosphoric Monoester Hydrolases
Carcinogenesis
Chemical shift
Transcription
Adenosine Triphosphate
Escherichia coli
Mutation
Substitution reactions
Nuclear magnetic resonance
8-oxodeoxyguanosine triphosphate
DNA
triphosphoric acid

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. / Sakai, Yasunari; Furuichi, Masato; Takahashi, Masayuki; Mishima, Masaki; Iwai, Shigenori; Shirakawa, Masahiro; Nakabeppu, Yusaku.

:: Journal of Biological Chemistry, 巻 277, 番号 10, 08.03.2002, p. 8579-8587.

研究成果: ジャーナルへの寄稿記事

Sakai, Yasunari ; Furuichi, Masato ; Takahashi, Masayuki ; Mishima, Masaki ; Iwai, Shigenori ; Shirakawa, Masahiro ; Nakabeppu, Yusaku. / A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. :: Journal of Biological Chemistry. 2002 ; 巻 277, 番号 10. pp. 8579-8587.
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