Hysteresis and Allostery in Human UDP-Glucose Dehydrogenase Require a Flexible Protein Core.

ABSTRACT: Human UDP-glucose dehydrogenase (hUGDH) oxidizes UDP-glucose to UDP-glucuronic acid, an essential substrate in the phase II metabolism of drugs. The activity of hUGDH is regulated by the conformation of a buried allosteric switch (T131 loop/α6 helix). Substrate binding induces the allosteric switch to slowly isomerize from an inactive E* conformation to the active E state, which can be observed as enzyme hysteresis. When the feedback inhibitor UDP-xylose binds, the allosteric switch and surrounding residues in the protein core repack, converting the hexamer into an inactive, horseshoe-shaped complex (E^Ω). This allosteric transition is facilitated by large cavities and declivities in the protein core that provide the space required to accommodate the alternate packing arrangement

SUBMITTER: Beattie NR 

PROVIDER: S-EPMC6312000 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature