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Research ArticleArticle

Interaction of Periodate-Oxidized UDP-Glucuronic Acid with Recombinant Human Liver UDP-Glucuronosyltransferase 1A6

Eric Battaglia, Nadege Terrier, Magdalena Mizeracka, Claire Senay, Jacques Magdalou, Sylvie Fournel-Gigleux and Anna Radominska-Pandya
Drug Metabolism and Disposition August 1998, 26 (8) 812-817;
Eric Battaglia
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Nadege Terrier
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Magdalena Mizeracka
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Claire Senay
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Jacques Magdalou
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Sylvie Fournel-Gigleux
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Anna Radominska-Pandya
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Abstract

Sodium periodate reacts with UDP-glucuronic acid (UDP-GlcUA) to generate a reactive derivative [periodate-oxidized UDP-GlcUA (o-UDP-GlcUA)]. The ability of this analog of UDP-GlcUA to inactivate and label the human recombinant UDP-glucuronosyltransferase (UGT) UGT1A6 via the UDP-GlcUA binding site was investigated. At an o-UDP-GlcUA concentration of 20 mM, the enzymatic activity of UGT1A6 was totally inactivated after 30 min of incubation at pH 7.4. Inhibition was irreversible, time-dependent, and concentration-dependent and exhibited pseudo-first order kinetics (kinact = 4.0 M−1·min−1). Cosubstrate protection with UDP-GlcUA was biphasic, with no protection in the first phase and almost total protection in the second phase, suggesting that at least 65% of the cross-linking occurs at the cosubstrate binding site. Partial inactivation byo-UDP-GlcUA led to a decrease inVmax, suggesting thato-UDP-GlcUA can act as an active site-directed inhibitor. Furthermore, proteins, including the UGTs, from membrane fractions of a recombinant V79 cell line expressing the UGT1A6 enzyme and from rat liver microsomes were cross-linked by in situ periodate oxidation of [β-32P]UDP-GlcUA. The present results suggest that periodate-oxidized UDP-GlcUA, which inactivates UGT1A6 by the possible formation of a Schiff base adduct with active site lysyl residues, can be used as a new affinity label for the UDP-GlcUA binding site.

Footnotes

  • Send reprint requests to: Anna Radominska-Pandya, Division of Gastroenterology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 567–1, Little Rock, AR 72205.

  • ↵1 This work was completed while N.T. was a student at Laboratoire de Biochimie Métabolique et Cellulaire, UFR SciFA, Université de Metz (Metz, France).

  • This work was supported in part by National Institutes of Health Grants DK45123 and DK49715 (to A.R.-P.).

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    ER
    endoplasmic reticulum
    SDS
    sodium dodecyl sulfate
    PAGE
    polyacrylamide gel electrophoresis
    UDP-GlcUA
    UDP-glucuronic acid
    o-UDP-GlcUA
    periodate-oxidized UDP-glucuronic acid
    5N3-UDP-GlcUA
    5-azido-UDP-glucuronic acid
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    • Received December 22, 1997.
    • Accepted April 17, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Research ArticleArticle

Interaction of Periodate-Oxidized UDP-Glucuronic Acid with Recombinant Human Liver UDP-Glucuronosyltransferase 1A6

Eric Battaglia, Nadege Terrier, Magdalena Mizeracka, Claire Senay, Jacques Magdalou, Sylvie Fournel-Gigleux and Anna Radominska-Pandya
Drug Metabolism and Disposition August 1, 1998, 26 (8) 812-817;

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Research ArticleArticle

Interaction of Periodate-Oxidized UDP-Glucuronic Acid with Recombinant Human Liver UDP-Glucuronosyltransferase 1A6

Eric Battaglia, Nadege Terrier, Magdalena Mizeracka, Claire Senay, Jacques Magdalou, Sylvie Fournel-Gigleux and Anna Radominska-Pandya
Drug Metabolism and Disposition August 1, 1998, 26 (8) 812-817;
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