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Originally published In Press as doi:10.1074/jbc.M110566200 on December 27, 2001
J. Biol. Chem., Vol. 277, Issue 10, 8579-8587, March 8, 2002
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¶, and
Yusaku
Nakabeppu **
From the Division of Neurofunctional Genomics,
Medical Institute of Bioregulation, Kyushu University and CREST, Japan
Science and Technology Corporation, Fukuoka 812-8582, Japan,
§ Research Group FRE 2230, CNRS and Université de
Nantes, 44322 Nantes, France, the ¶ Division of Molecular
Biophysics, Science of Biological Supramolecular Systems, Graduate
School of Integrated Science, Yokohama City University, Yokohama
231-0045, Japan, and the Biological Engineering Research
Institute, Osaka 565-0874, Japan
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.
*
This work was supported in part by a grant-in-aid for
scientific research from the Ministry of Education, Science, Sports and
Culture of Japan.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
**
To whom correspondence should be addressed. Tel.: 81-92-642-6800;
Fax: 81-92-642-6791; E-mail:
yusaku@bioreg.kyushu-u.ac.jp.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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