Hydrolyzes nucleoside diphosphates with a preference for GDP, IDP and UDP compared to ADP and CDP (PubMed:10369669, PubMed:21074248). In the lumen of the endoplasmic reticulum, hydrolyzes UDP that acts as an end-product feedback inhibitor of the UDP-Glc:glycoprotein glucosyltransferases. UMP can be transported back by an UDP-sugar antiporter to the cytosol where it is consumed to regenerate UDP-glucose (PubMed:21074248). Therefore, it positively regulates protein reglucosylation by clearing UDP from the ER lumen and by promoting the regeneration of UDP-glucose (PubMed:21074248). Protein reglucosylation is essential to proper glycoprotein folding and quality control in the ER (PubMed:21074248). a ribonucleoside 5'-diphosphate + H2O = a ribonucleoside 5'-phosphate + H(+) + phosphate GDP + H2O = GMP + H(+) + phosphate H2O + UDP = H(+) + phosphate + UMP H2O + IDP = H(+) + IMP + phosphate CDP + H2O = CMP + H(+) + phosphate ADP + H2O = AMP + H(+) + phosphate Optimum pH is 7. Protein modification; protein glycosylation. Monomer; active form. Homodimer; disulfide-linked. Homodimers are enzymatically inactive. Ubiquitous. Expressed in response to phosphoinositide 3-kinase (PI3K) signaling. Activation of PI3K results in FOXO phosphorylation by AKT1 and loss of ENTPD5 transcriptional repression. Up-regulated in PTEN-deficient cells. N-glycosylated; high-mannose type. Mice display hepatopathy and aspermia. The hepatopathy is progressive and characterized by centrilobular hepatocyte hypertrophy, oval cell proliferation, bile staining of Kupffer cells, and hepatocyte degeneration with increasing incidence and severity of degenerative lesions, development of multiple foci of cellular alteration, and hepatocellular neoplasia with age. Belongs to the GDA1/CD39 NTPase family.