Nudix hydrolase 15 (NUDT15)

Nudix hydrolase 15 (NUDT15) is a member of the NUDIX hydrolase family of enzymes, functioning as a pyrophosphohydrolase that prefers nucleotide substrates including active thiopurine metabolites such as 6-thio-deoxyGTP. NUDT15 plays an essential role in pharmacogenetics, as it regulates the activation and toxicity of thiopurine drugs widely used for cancer and inflammatory disease treatment. Germline variants, particularly the R139C mutation, are strongly associated with enhanced sensitivity to thiopurines, leading to potentially severe leukopenia and other toxicities if unadjusted doses are administered. NUDT15 is a homodimeric enzyme with a classical NUDIX fold, structurally distinct from its family member MTH1, as it displays selectivity for different nucleotide substrates and lacks strong activity toward oxidized guanine species. Clinical guidelines now incorporate NUDT15 genotyping to personalize thiopurine therapy[1][2][3][5].

Other names

Nucleotide triphosphate diphosphatase NUDT15MTH2Nudix motif 15FLJ10956MutT homolog 2Nucleoside diphosphate-linked moiety X motif 15Nucleoside diphosphate-linked to another moiety X hydrolase 15NUDT15D8-oxo-dGTPase NUDT15probable 7,8-dihydro-8-oxoguanine triphosphatase NUDT15probable 8-oxo-dGTP diphosphatase NUDT15nudix (nucleoside diphosphate linked moiety X)-type motif 15

Drugs like thiopurines are metabolized to active nucleotides (e.g., 6-thio-dGTP); NUDT15 hydrolyzes these active metabolites, reducing their incorporation into DNA and modulating efficacy and toxicity[4][5]. Inhibitors of NUDT15 (TH1760, TH7755) potentiate the effect of thiopurines by allowing active metabolites to accumulate in DNA[5].