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UDP-glucose analogues as inhibitors and mechanistic probes of UDP-glucose dehydrogenase

TitleUDP-glucose analogues as inhibitors and mechanistic probes of UDP-glucose dehydrogenase
Publication TypeJournal Article
Year of Publication1999
AuthorsCampbell, RE, Tanner, ME
JournalJournal of Organic Chemistry
Volume64
Pagination9487-9492
Date PublishedDec
Type of ArticleArticle
ISBN Number0022-3263
KeywordsEFFICIENT SYNTHESIS, FUCOSE, GROUP-A STREPTOCOCCI, nucleotides, POLYSACCHARIDE, VIRULENCE
Abstract

UDP-glucose dehydrogenase catalyzes the NAD(+)-dependent 2-fold oxidation of UDP-glucose to give UDP-glucuronic acid. The putative aldehyde intermediate is not released from the active site and is presumably tightly bound. We have prepared UDP-7-deoxy-alpha-D-gluco-hept-6-ulopyranose 5, that contains a methyl ketone at C-6 and cannot be further oxidized by the enzyme. Ketone 5 was found to be a competitive inhibitor of the dehydrogenase from Streptococcus pyogenes with a K-I value of 6.7 mu M. We have also prepared the secondary alcohols UDP-6S-6C-methylglucose, 4a, and UDP-6R-6C-methylglucose, 4b. Compound 4a, but not 4b, was found to be a slow substrate for the dehydrogenase and was converted into the ketone inhibitor 5. This is consistent with the notion that the pro-R hydride is transferred in the first oxidation step of the normal enzymatic reaction.

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