TY - JOUR
T1 - Recognition of nucleotide analogs containing the 7,8-dihydro-8-oxo structure by the human MTH1 protein
AU - Kamiya, Hiroyuki
AU - Cadena-Amaro, Claudio
AU - Dugué, Laurence
AU - Yakushiji, Hiroyuki
AU - Minakawa, Noriaki
AU - Matsuda, Akira
AU - Pochet, Sylvie
AU - Nakabeppu, Yusaku
AU - Harashima, Hideyoshi
N1 - Funding Information:
We thank Ms. H. Matsumoto and Ms. S. Oka (Center for Instrumental Analysis, Hokkaido University) for technical assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. C.N.R.S. (URA 2128) and Pasteur Institute (Paris) are acknowledged for financial support. C. C.-A. is grateful to the CONACYT (Mexico) for a doctoral scholarship.
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
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U2 - 10.1093/jb/mvj214
DO - 10.1093/jb/mvj214
M3 - Article
C2 - 17071637
AN - SCOPUS:34250650140
SN - 0021-924X
VL - 140
SP - 843
EP - 849
JO - Journal of biochemistry
JF - Journal of biochemistry
IS - 6
ER -