Recognition of nucleotide analogs containing the 7,8-dihydro-8-oxo structure by the human MTH1 protein.
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.
Kamiya
Hiroyuki
H
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812. hirokam@pharm.hoku-dai.ac.jp
Cadena-Amaro
Claudio
C
Dugué
Laurence
L
Yakushiji
Hiroyuki
H
Minakawa
Noriaki
N
Matsuda
Akira
A
Pochet
Sylvie
S
Nakabeppu
Yusaku
Y
Harashima
Hideyoshi
H
D045643:DNA Repair Enzymes / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000138:chemical synthesis / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000138:chemical synthesis / Q000378:metabolism*; D003854:Deoxyribonucleotides / Q000138:chemical synthesis / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C517297:1-(2-deoxyribofuranosyl)-2,3-dihydro-2-oxoimidazole-4-carboxamide 5'-triphosphate; C517296:2-amino-9-(2-deoxyribofuranosyl)-7,8-dihydro-8-oxopurine 5'-triphosphate; D003838:Deoxyadenine Nucleotides; D003848:Deoxyguanine Nucleotides; D003854:Deoxyribonucleotides; D007093:Imidazoles; C517298:N6-(2-deoxyribofuranosyl)-2,6-diamino-5-formamido-4-hydroxypyrimidine 5'-triphosphate; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes