Cryo-EM Structure of Recombinantly Expressed hUGDH Unveils a Hidden, Alternative Allosteric Inhibitor.

ABSTRACT: Human UDP-glucose dehydrogenase (hUGDH) catalyzes the oxidation of UDP-glucose into UDP-glucuronic acid, an essential substrate in the Phase II metabolism of drugs. hUGDH is a hexamer that exists in an equilibrium between an active (E) state and an inactive (E^Ω) state, with the latter being stabilized by the binding of the allosteric inhibitor UDP-xylose (UDP-Xyl). The allosteric transition between E^Ω and E is slow and can be observed as a lag in progress curves. Previous analysis of the lag suggested that unliganded hUGDH exists mainly as E^Ω, but two unique crystal forms suggest that the enzyme favors the E state. Resolving this discrepancy is necessary to fully understand the allosteric mechanism of hUGDH. Here, we used cryo-EM to show that recombinant hU

SUBMITTER: O'Brien JH 

PROVIDER: S-EPMC11713868 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature