8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog.
The human mutT homolog, hMTH1, suppresses spontaneous mutations by degrading the endogeneous mutagen, 8-hydroxy-dGTP. We previously reported the broad substrate specificity of hMTH1, which also degrades the oxidatively damaged purine nucleotides, 2-hydroxy-dATP, 8-hydroxy-dATP, 2-hydroxy-ATP, and 8-hydroxy-GTP, in addition to 8-hydroxy-dGTP. In this paper, we describe the hMTH1 activity for 8-chloro-dGTP, which could be formed in inflamed tissue by the reaction of dGTP with hypochlorous acid, a product of myeloperoxidase from activated human neutrophils. The hMTH1 protein was mixed with 1-20 microM of 8-chloro-dGTP and 8-hydroxy-dGTP, and the reaction products were quantified by anion-exchange HPLC to measure the pyrophosphatase reaction rate. The kinetic parameters revealed that 8-chloro-dGTP was degraded by hMTH1 with 50% efficiency as compared with that of 8-hydroxy-dGTP. This result suggests that 8-chloro-dGTP is an intrinsic substrate for hMTH1.
Fujikawa
Katsuyoshi
K
Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, 807-8555, Kitakyushu, Japan.
Yakushiji
Hiroyuki
H
Nakabeppu
Yusaku
Y
Suzuki
Toshinori
T
Masuda
Mitsuharu
M
Ohshima
Hiroshi
H
Kasai
Hiroshi
H
D001426:Bacterial Proteins / Q000235:genetics; D045643:DNA Repair Enzymes; D029968:Escherichia coli Proteins; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D006997:Hypochlorous Acid; D009711:Nucleotides / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
C450421:8-chloro-2'-deoxyguanosine triphosphate; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D009711:Nucleotides; C057674:8-hydroxyguanosine triphosphate; D006997:Hypochlorous Acid; D006160:Guanosine Triphosphate; D010744:Phosphoric Monoester Hydrolases; D011755:Pyrophosphatases; C052211:mutT protein, E coli; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes