Glucuronidation is a major detoxification pathway in the Phase II metabolism of drugs, and is often the source of unfavorable pharmacokinetics or pharmacodynamics during clinical trials; the rapid clearance of a drug reduces bioavailability, and the resulting glucuronides can be toxic. In addition, some cancers have been shown to co-opt glucuronidation as an effective drug resistance mechanism. It is known that glucuronidation can be controlled through substrate availability. Thus, there is a critical need to understand the mechanisms that regulate the levels of UDP-glucuronic acid (UDP-GlcA), the essential substrate in glucuronidation.
Human UDP-glucose 6-dehydrogenase (hUGDH) catalyzes the NAD+ dependent oxidation of UDP-glucose to UDP-GlcA. In addition to its role in drug metabolism, UDP-GlcA is also the substrate for the biosynthesis of UDP-xylose, which acts as an allosteric feedback inhibitor for hUGDH. In addition to allostery, hUGDH undergoes substrate-induced hysteresis (a slow isomerization of the enzyme from an inactive state to an active conformation). Our goal is to determine the allosteric and hysteretic mechanisms that control hUGDH activity.