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Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase)

Target: dUTPase
Molecular classification: Enzyme, Hydrolase (acting on acid anhydrides, particularly phosphorus-containing anhydrides)

Overview

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is an essential enzyme that hydrolyzes dUTP to dUMP and inorganic pyrophosphate, thereby providing dUMP for thymidylate (thymine nucleotide) synthesis and limiting the cellular pool of dUTP. This dual function prevents incorporation of uracil into DNA, which would otherwise induce extensive and futile DNA repair cycles, DNA fragmentation, and cell death. dUTPase plays a central role in nucleotide metabolism and DNA replication in all dividing cells. It is explored as a potential drug target in protozoal infections (e.g., malaria) and is of interest in cancer and other diseases where nucleotide metabolism is dysregulated.

Other names: dUTP diphosphataseDeoxyuridine-triphosphatasedUTPasedUTP pyrophosphataseDesoxyuridine 5'-triphosphate nucleotidohydrolaseDesoxyuridine 5'-triphosphatase

Mechanism of action

Inhibition of dUTPase reduces the removal of dUTP from the nucleotide pool, leading to uracil incorporation in DNA, subsequent DNA fragmentation, and cell death in target organisms or tumor cells

Biological functions

Pyrimidine metabolismMaintenance of DNA integrity (prevents uracil misincorporation into DNA)Precursor production for thymidylate biosynthesisRegulation of deoxynucleotide pool balance

Disease associations

Cancer (DNA integrity and repair, potential sensitivity to antifolate therapy)Infection (antiparasitic drug target for protozoa, e.g., Plasmodium falciparum)Bone marrow failure and diabetes mellitus syndrome (genetic association)Other: Epstein-Barr virus infectious disease (disease association)

Safety considerations

Targeting human dUTPase may cause toxicity due to DNA damage in rapidly dividing normal cells, including bone marrow and gastrointestinal mucosaSelectivity for pathogenic over human dUTPase is crucial in antiparasitic or anticancer drug development

Interacting drugs

5'-tritylamino-2',5'-dideoxyuridine (experimental, antiprotozoal)

2 more in the full profile.

Biomarkers

dUTPase expression level may predict sensitivity to antifolate drugs or inhibitors (mainly in experimental/biomarker development settings)No widely approved clinical biomarkers at present

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