posted on 1999-12-03, 00:00authored byRobert E. Campbell, Martin E. Tanner
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-α-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 KI value of
6.7 μM. 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.