Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) (dUTPase)

Human dUTPase (deoxyuridine 5'-triphosphate nucleotidohydrolase) is a critical enzyme in the nucleotide metabolism pathway, responsible for hydrolyzing dUTP into dUMP and inorganic pyrophosphate (UniProt P33316). This dual-function reaction provides the essential precursor for thymidylate synthesis while simultaneously preventing the accumulation of dUTP, thereby minimizing the misincorporation of uracil into DNA (PubMed: 25650004). In many malignancies, such as colorectal and non-small cell lung cancers, dUTPase is overexpressed and serves as a resistance mechanism against thymidylate synthase inhibitors like 5-fluorouracil (PubMed: 21810914). By inhibiting dUTPase with small molecules like TAS-114, the intracellular dUTP/dTTP ratio increases significantly, leading to extensive uracil misincorporation and subsequent DNA damage through futile repair cycles (PubMed: 24954411). This targeted approach sensitizes tumor cells to antimetabolite chemotherapy and represents a promising strategy for overcoming drug resistance in clinical oncology (PubMed: 28446464).

Other names

DUTdUTP pyrophosphatasedUTPaseDeoxyuridine pyrophosphate diglycosylase

Inhibition of dUTPase leads to an increase in intracellular dUTP levels, which are then misincorporated into DNA in place of dTTP. This triggers the base excision repair (BER) pathway, specifically uracil-DNA glycosylase (UNG), leading to repetitive cycles of repair, DNA strand breaks, and apoptosis (PubMed: 24954411).