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-oxo-dGDP) 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 microM), dADP (Ki=147 microM), and
GDP (Ki=502 microM). 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 microM and
GDP at mean concentration of 30 microM, 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.