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Journal of Biochemistry Advance Access published online on October 27, 2006
Journal of Biochemistry, doi:10.1093/jb/mvj214
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© 2006 The Japanese Biochemical Society.
Received September 20, 2006
Accepted October 24, 2006

Regular Paper

Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein

Hiroyuki Kamiya 1 *, Claudio Cadena-Amaro 2, Laurence Dugué 2, Hiroyuki Yakushiji 3, Noriaki Minakawa 1, Akira Matsuda 1, Sylvie Pochet 2, Yusaku Nakabeppu 3, and Hideyoshi Harashima 1

1 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
2 Unité de Chimie Organique, Institut Pasteur, 28, rue Dr Roux, 75724 Paris cedex 15, France
3 Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

* To whom correspondence should be addressed.
Hiroyuki Kamiya, E-mail: hirokam{at}pharm.hokudai.ac.jp


  Abstract

The MTH1 protein catalyzes hydrolysis of oxidatively damaged purine nucleotides including 8-hydroxy-dGTP to the monophosphates. The MTH1 protein seems to act as an important defense system against mutagenesis, carcinogenesis, and cell death induced by oxidized purine nucleotides. We previously reported that the functional groups at the 2- and 6-positions of the purine ring affect the recognition by the human MTH1 protein. 8-Hydroxy-dGTP and 8-hydroxy-dATP are substrates of MTH1, and both have the ‘7,8-dihydro-8-oxo structure’. In this study, three nucleotide analogs containing this motif were examined. A synthetic purine analog containing the 7,8-dihydro-8-oxo structure and the 2-amino function (dJTP) was hydrolyzed to the monophosphate with high efficiency by MTH1. On the other hand, two analogs that lack the two-ring system of their bases (formamidopyrimidine-dGTP (FAPY-dGTP) and 2-OH-dYTP) were poor substrates. FAPY-dGTP is a mixture of conformers and was hydrolyzed more than ten-fold less efficiently than 8-hydroxy-dGTP. These results clarify the effects of the 2-amino group and the two-ring system of the purine base on the recognition by the human MTH1 protein.

Keywords: FAPY-dGTP; MTH1; nucleotide analog; oxidized nucleotide; substrate recognition.
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