Conservation of Atypical Allostery in C. elegans UDP-Glucose Dehydrogenase

Beattie, Nathaniel R.; Keul, Nicholas D.; Hicks Sirmans, Tiffany N.; McDonald, Weston E.; Talmadge, Trevor M.; Taujale, Rahil; Kannan, Natarajan; Wood, Zachary A.

doi:10.1021/acsomega.9b01565

Title: Conservation of Atypical Allostery in C. elegans UDP-Glucose Dehydrogenase

Journal Article · Tue Sep 24 00:00:00 EDT 2019 · ACS Omega

DOI:https://doi.org/10.1021/acsomega.9b01565· OSTI ID:1573404

Beattie, Nathaniel R. ^[1]; Keul, Nicholas D. ^[1]; Hicks Sirmans, Tiffany N. ^[1]; McDonald, Weston E. ^[1]; Talmadge, Trevor M. ^[1]; Taujale, Rahil ^[1]; Kannan, Natarajan ^[1];

^[1]

Univ. of Georgia, Athens, GA (United States)

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^Ω). 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: W-31-109-Eng-3; R01GM114298; S10RR25528; S10RR028976; S10OD021762

OSTI ID:: 1573404

Journal Information:: ACS Omega, Vol. 4, Issue 15; ISSN 2470-1343

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 4 works

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