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TitleCryo-EM Structure of Recombinantly Expressed hUGDH Unveils a Hidden, Alternative Allosteric Inhibitor.
Journal, issue, pagesBiochemistry, Vol. 64, Issue 1, Page 92-9104, Year 2025
Publish dateJan 7, 2025
AuthorsJohn H O'Brien / Renuka Kadirvelraj / Po-Sen Tseng / Nolan Ross-Kemppinen / David Crich / Richard M Walsh / Zachary A Wood /
PubMed AbstractHuman 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 ...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) state, with the latter being stabilized by the binding of the allosteric inhibitor UDP-xylose (UDP-Xyl). The allosteric transition between E 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, 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 hUGDH expressed in copurifies with UDP-4-keto-xylose (UX4O), which mimics the UDP-Xyl inhibitor and favors the E state. Cryo-EM studies show that removing UX4O from hUGDH shifts the ensemble to favor the E state. This shift is consistent with progress curve analysis, which shows the absence of a lag for unliganded hUGDH. Inhibition studies show that hUGDH has similar affinities for UDP-Xyl and UX4O. The discovery that UX4O inhibits allosteric hUGDH suggests that UX4O may be the physiologically relevant inhibitor of allosteric UGDHs in bacteria that do not make UDP-Xyl.
External linksBiochemistry / PubMed:39680853 / PubMed Central
MethodsEM (single particle)
Resolution2.06 - 2.38 Å
Structure data

46853

9dgz

EMDB-46853, PDB-9dgz:
The Cryo-EM structure of recombinantly expressed apo hUGDH
Method: EM (single particle) / Resolution: 2.06 Å

46854

9dh0

EMDB-46854, PDB-9dh0:
The Cryo-EM structure of recombinantly expressed hUGDH in complex with UDP-4-keto-xylose
Method: EM (single particle) / Resolution: 2.38 Å

Chemicals

ChemComp-HOH:
WATER

PDB-1bcu:
ALPHA-THROMBIN COMPLEXED WITH HIRUGEN AND PROFLAVIN

Source
  • homo sapiens (human)
KeywordsOXIDOREDUCTASE / Unliganded human UDP-Glucose Dehydrogenase / OXIDOREDUCTASE/INHIBITOR / Human UDP-Glucose Dehydrogenase / UDP-4-keto-xylose / OXIDOREDUCTASE-INHIBITOR complex

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