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Publication Abstract from PubMed

Human UDP-glucose dehydrogenase (hUGDH) oxidizes uridine diphosphate (UDP)-glucose to UDP-glucuronic acid, an essential substrate in the phase II metabolism of drugs. The activity of hUGDH is controlled by an atypical allosteric mechanism in which the feedback inhibitor UDP-xylose competes with the substrate for the active site and triggers a buried allosteric switch to produce an inactive complex (E(Omega)). Previous comparisons with a nonallosteric UGDH identified six large-to-small substitutions that produce packing defects in the protein core and provide the conformational flexibility necessary for the allosteric transition. Here, we test the hypothesis that these large-to-small substitutions form a motif that can be used to identify allosteric UGDHs. Caenorhabditis elegans UGDH (cUGDH) conserves this motif with the exception of an Ala-to-Pro substitution in position 109. The crystal structures of unliganded and UDP-xylose bound cUGDH show that the A109P substitution is accommodated by an Asn-to-Ser substitution at position 290. Steady-state analysis and sedimentation velocity studies show that the allosteric transition is conserved in cUGDH. The enzyme also exhibits hysteresis in progress curves and negative cooperativity with respect to NAD(+) binding. Both of these phenomena are conserved in the human enzyme, which is strong evidence that these represent fundamental features of atypical allostery in UGDH. A phylogenetic analysis of UGDH shows that the atypical allostery motif is ancient and identifies a potential transition point in the evolution of the UGDH family.

Conservation of Atypical Allostery in C. elegans UDP-Glucose Dehydrogenase.,Beattie NR, Keul ND, Hicks Sirmans TN, McDonald WE, Talmadge TM, Taujale R, Kannan N, Wood ZA ACS Omega. 2019 Sep 24;4(15):16318-16329. doi: 10.1021/acsomega.9b01565., eCollection 2019 Oct 8. PMID:31616809^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.