Deoxyuridine Triphosphate Nucleotidohydrolase (DUT) Enzyme

This gene encodes an essential enzyme of nucleotide metabolism. The encoded protein forms a ubiquitous, homotetrameric enzyme that hydrolyzes dUTP to dUMP and pyrophosphate. This reaction serves two cellular purposes: providing a precursor (dUMP) for the synthesis of thymine nucleotides needed for DNA replication, and limiting intracellular pools of dUTP. Elevated levels of dUTP lead to increased incorporation of uracil into DNA, which induces extensive excision repair mediated by uracil glycosylase. This repair process, resulting in the removal and reincorporation of dUTP, is self-defeating and leads to DNA fragmentation and cell death. Alternative splicing of this gene leads to different isoforms that localize to either the mitochondrion or nucleus. A related pseudogene is located on chromosome 19. [provided by RefSeq, Jul 2008]

Function: This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. Ref.21

Catalytic activity: dUTP + H2O = dUMP + diphosphate. Ref.21

Cofactor: Magnesium. Ref.21

Enzyme regulation: Phosphorylation is necessary for activity.

Pathway: Pyrimidine metabolism; dUMP biosynthesis; dUMP from dCTP (dUTP route): step 2/2.

Subunit structure: Homotrimer. Ref.21 Ref.22

Subcellular location: Isoform 2: Nucleus Ref.1 Ref.4. Isoform 3: Mitochondrion Ref.1 Ref.4.

Tissue specificity: Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level). Ref.4

Post-translational modification: Nuclear isoform 2 is phosphorylated in vivo on Ser-11, a reaction that can be catalyzed in vitro by CDC2. Phosphorylation in mature T-cells occurs in a cell cycle-dependent manner. Isoform 3 is not phosphorylated. Ref.13 Ref.14The initiator methionine is cleaved in isoform 2. Ref.1

Miscellaneous: Each trimer binds three substrate molecules. The ligands are bound between subunits, and for each substrate molecule, residues from adjacent subunits contribute to the binding interactions.

Sequence similarities: Belongs to the dUTPase family.

Biophysicochemical propertiesKinetic parameters:for both isoform 2 and isoform 3.KM=2.5 µM for dUTP Ref.1

Sequence caution: The sequence AAB71393.1 differs from that shown. Reason: Frameshift at positions 29 and 47. The sequence AAB93866.1 differs from that shown. Reason: Frameshift at positions 29 and 47. The sequence AAB94642.1 differs from that shown. Reason: Frameshift at positions 29 and 47.