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. One strategy for regulating glucuronidation is controlling the availability of the essential substrate, UDP-glucuronic acid (UDP-GlcA). By reducing UDP-GlcA levels, it should possible to sensitize those drug resistant cancers that utilize 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). My lab uses structural biology and enzymology to understand the allosteric and hysteretic mechanisms that control hUGDH activity. Our ultimate goal is to leverage these mechanisms to control UDP-GlcA levels.

Pubmed