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Inhibition of 8-oxo-2 '-deoxyguanosine 5 '-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) activity of the antimutagenic human MTH1 protein by nucleoside 5 '-diphosphates

  1. Author:
    Bialkowski, K.
    Kasprzak, K. S.

  2. Author Address

    Ludwik Rydygier Med Univ, Dept Clin Biochem, Karlowicza 24, PL- 85092 Bydgoszcz, Poland Ludwik Rydygier Med Univ, Dept Clin Biochem, PL-85092 Bydgoszcz, Poland Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD USA Bialkowski K Ludwik Rydygier Med Univ, Dept Clin Biochem, Karlowicza 24, PL-85092 Bydgoszcz, Poland
    1. Year: 2003
  2. Journal: Free Radical Biology and Medicine
    1. 35
    2. 6
    3. Pages: 595-602
  4. Type of Article: Article
  1. Abstract:

    The hMTH1 protein, a human homologue of E. coli MutT protein, is an enzyme converting 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) to 8-oxo-2'-deoxyguanosine 5'-monophosphate (8- oxo-dGMP) and inorganic pyrophosphate. It is thought to play an antimutagenic role by preventing, the incorporation of promutagenic 8-oxo-dGTP into DNA. As found in our previous investigations, 8-oxo-2'-deoxyguanosine 5'-diphosphate (8-oxod- GDP) strongly inhibited 8-oxo-dGTPase activity of MTH1. Following this finding, in the present study we have tested the canonical ribo- and deoxyribonucleoside 5'-diphosphates (NDPs and dNDPs) for possible inhibition of 8-oxo-dGTP hydrolysis by hMTH1 extracted from CCRF-CEM cells (a human leukemia cell line). Among them, the strongest inhibitors appeared to be dGDP (Ki = 74 muM), dADP (Ki = 147 muM), and GDP (Ki = 502 muM). Other dNDPs and NDPs, such as dCDP, dTDP, ADP, CDP, and UDP were much weaker inhibitors, with Ki in the millimolar range. Based on the present results and published data, we estimate that the strongest inhibitors, dGDP and dADP. at physiological concentrations not exceeding 5 AM and GDP at mean concentration of 30 AM, taken together, can decrease the cellular hMTH1 enzymatic activity vs. 8-oxo-dGTP (expected to remain below 500 pM) by up to 15%. The other five NDPs and dNDPs tested cannot markedly affect this activity. (C) 2003 Elsevier.

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