Structure of human MTH1, a nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates

Masaki Mishima, Yasunari Sakai, Noriyuki Itoh, Hiroyuki Kamiya, Masato Furuichi, Masayuki Takahashi, Yuriko Yamagata, Shigenori Iwai, Yusaku Nakabeppu, Masahiro Shirakawa

研究成果: ジャーナルへの寄稿記事

41 引用 (Scopus)

抄録

Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (∼9 Å) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn33 as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the β-phosphate.

元の言語英語
ページ(範囲)33806-33815
ページ数10
ジャーナルJournal of Biological Chemistry
279
発行部数32
DOI
出版物ステータス出版済み - 8 6 2004

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Purine Nucleosides
Hydrolases
Cell Respiration
Biomolecular Nuclear Magnetic Resonance
Mutation
Proteins
Chemical shift
Substrates
Substrate Specificity
Mitochondrial DNA
Escherichia coli
Nuclear magnetic resonance spectroscopy
Hydrolysis
Reactive Oxygen Species
Substitution reactions
Magnetic Resonance Spectroscopy
Nucleotides
Phosphates
Water
triphosphoric acid

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

Structure of human MTH1, a nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. / Mishima, Masaki; Sakai, Yasunari; Itoh, Noriyuki; Kamiya, Hiroyuki; Furuichi, Masato; Takahashi, Masayuki; Yamagata, Yuriko; Iwai, Shigenori; Nakabeppu, Yusaku; Shirakawa, Masahiro.

:: Journal of Biological Chemistry, 巻 279, 番号 32, 06.08.2004, p. 33806-33815.

研究成果: ジャーナルへの寄稿記事

Mishima, Masaki ; Sakai, Yasunari ; Itoh, Noriyuki ; Kamiya, Hiroyuki ; Furuichi, Masato ; Takahashi, Masayuki ; Yamagata, Yuriko ; Iwai, Shigenori ; Nakabeppu, Yusaku ; Shirakawa, Masahiro. / Structure of human MTH1, a nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. :: Journal of Biological Chemistry. 2004 ; 巻 279, 番号 32. pp. 33806-33815.
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