UDP-glucose 6-dehydrogenase (UGDH)

UDP-glucose 6-dehydrogenase (UGDH) is a cytosolic enzyme encoded by the UGDH gene in humans. It catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronic acid, a key step in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate—critical components of the extracellular matrix involved in cell migration, signal transduction, and cancer progression. UGDH is structured as a trimer of homodimers, with active sites formed at the interdomain cleft between distinct α/β domains. Its expression is regulated by factors such as transforming growth factor beta and hypoxia. Loss of function mutations are implicated in genetic disorders like epileptic encephalopathy, while elevated enzyme activity is associated with cancers, making it a putative target for cancer therapy, particularly via inhibition of UDP-glucuronic acid synthesis. However, its fundamental role in essential biological processes presents therapeutic challenges regarding safety and tolerability.

Other names

UDP-glucose dehydrogenaseuridine diphosphoglucose dehydrogenaseUDPG dehydrogenaseUDPG:NAD oxidoreductaseUDP-alpha-D-glucose:NAD oxidoreductaseUDP-glucose:NAD+ oxidoreductaseuridine diphosphate glucose dehydrogenaseUDP-D-glucose dehydrogenaseuridine diphosphate D-glucose dehydrogenase

Inhibition of UGDH blocks biosynthesis of UDP-glucuronic acid, thereby reducing glycosaminoglycan formation; possible drug mechanism would involve competitive or allosteric inhibition, most promisingly at the NAD+ binding domain