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M110566200v1
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Papers In Press, published online ahead of print December 27, 2001
J. Biol. Chem, 10.1074/jbc.M110566200
Submitted on November 2, 2001
Revised on December 21, 2001
Accepted on December 26, 2001

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

Division of Neurofunctional Genomics,, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582

Corresponding Author: yusaku{at}bioreg.kyushu-u.ac.jp

MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP and 2-hydroxy ATP 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 homologue, MutT which hydrolyzes only 8-oxo-dGTP and 8-oxoGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosophohydrolase 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 W117 and D119 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. W117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP while D119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.


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