Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP

The human nucleotide pool sanitization enzyme, MTH1, hydrolyzes 2-hydroxy-d ATP and 8-hydroxy-dATP in addition to 8-hydroxy-dGTP. We report here that h uman MTH1 is highly specific for a-hydroxy-ATP, among the cognate ribonucle oside triphosphates. The pyrophosphatase activities for 8-hydroxy-GTP, 2-hy droxy-ATP and 8-hydroxy-ATP were measured by high-performance liquid chroma tography, The kinetic parameters thus obtained indicate that the catalytic efficiencies of MTH1 are in the order of 2-hydroxy-dATP > 2-hydroxy-ATP > 8 -hydroxy-GTP > 8-hydroxy-dATP >> dGTP > 8-hydroxy-GTP > 8-hydroxy-ATP. Nota bly, MTH1 had the highest affinity for P-hydroxy-ATP among the known substr ates, ATP is involved in energy metabolism and signal transduction, and is a precursor in RNA synthesis. We suggest that the 2-hydroxy-ATP hydrolyzing activity of MTH1 might prevent the perturbation of these ATP-related pathw ays by the oxidized ATP.