Nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) (NUDT15)

Nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) is a member of the Nudix hydrolase family that functions as a pyrophosphatase (UniProt: Q9NV35). Its primary biological role is the hydrolysis of nucleoside triphosphates, specifically the active metabolites of thiopurine drugs such as 6-mercaptopurine and azathioprine (PubMed: 24562437). By converting 6-thio-GTP and 6-thio-dGTP into inactive monophosphates, NUDT15 prevents the incorporation of these toxic analogs into DNA, which would otherwise lead to cell cycle arrest and apoptosis (PubMed: 26878175). Genetic variants that reduce NUDT15 activity are strongly associated with severe, dose-limiting toxicities, including life-threatening myelosuppression and alopecia, particularly in Asian and Hispanic populations (PharmGKB: NUDT15). As a result, NUDT15 testing is clinically recommended by organizations like the Clinical Pharmacogenetics Implementation Consortium (CPIC) to guide thiopurine dosing in patients with inflammatory bowel disease or leukemia (PubMed: 30006871). Beyond its role as a pharmacogenetic marker, NUDT15 is being investigated as a therapeutic target in oncology. Small molecule inhibitors of NUDT15 can sensitize cancer cells to thiopurine therapy, potentially allowing for lower, more effective drug doses while overcoming resistance (PubMed: 29610580). This makes NUDT15 both a critical safety biomarker and a promising target for combination therapy strategies.

Other names

NUDIX15MTH2MutT homolog 27,8-dihydro-8-oxoguanine triphosphatase ASITHS

NUDT15 acts as a negative regulator of thiopurine drug activity by hydrolyzing the active metabolites 6-thio-GTP and 6-thio-dGTP into their inactive monophosphate forms, thereby preventing their incorporation into DNA and RNA (PubMed: 24562437). Small molecule inhibitors target the NUDT15 enzyme to prevent this hydrolysis, thereby sensitizing cells to the cytotoxic effects of thiopurines (PubMed: 29610580).