6OM8

Caenorhabditis Elegans UDP-Glucose Dehydrogenase in complex with UDP-Xylose

Summary for 6OM8

• Entry DOI: 10.2210/pdb6om8/pdb
• Descriptor: UDP-glucose 6-dehydrogenase, URIDINE-5'-DIPHOSPHATE-XYLOPYRANOSE (3 entities in total)
• Functional Keywords: dehydrogenase, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 12
• Total formula weight: 646614.72

Authors

Beattie, N.R.,McDonald, W.E.,Hicks Sirmans, T.N.,Wood, Z.A. (deposition date: 2019-04-18, release date: 2019-05-22, Last modification date: 2023-10-11)

Primary citation

Beattie, N.R.,Keul, N.D.,Hicks Sirmans, T.N.,McDonald, W.E.,Talmadge, T.M.,Taujale, R.,Kannan, N.,Wood, Z.A.
Conservation of Atypical Allostery inC. elegansUDP-Glucose Dehydrogenase.
Acs Omega, 4:16318-16329, 2019

PubMed Abstract: 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). 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. 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.

PubMed: 31616809
DOI: 10.1021/acsomega.9b01565

Experimental method

X-RAY DIFFRACTION (2.449 Å)