Meta-Biol

• Pathways

NUDT1 (MTH1) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been biochemically (Sakumi et al. 1993; Takagi et al. 2012) and structurally (Mishima et al. 2004) characterized and shown to catalyze hydrolysis of 8-oxo-dGTP. The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of oxo-guanine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003).

Together, these data support the hypothesis that by cleaving 8-oxo-dGTP and thus preventing its incorporation into DNA NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress.