# The role of intrinsic disorder in the allosteric regulation of human UGDH

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2023 · $7,039

## Abstract

PROJECT SUMMARY (UNCHANGED)
Glucuronidation is often the source of unfavorable pharmacokinetics or pharmacodynamics that lead to the
failure of drugs during clinical trials, and as such, there is a critical need in drug development for a tool to
control glucuronidation. Our long-term goal is to develop strategies to control glucuronidation by limiting its
substrate availability. To do this, we will determine the allosteric mechanism that controls human UDP-glucose
dehydrogenase (hUGDH), the enzyme that produces the essential substrate for glucuronidation. In our
previous grant, we discovered how the 30-residue intrinsically disordered C-terminus (the ID-tail) modifies the
structure of the enzyme to favor binding of the feedback inhibitor UDP-Xyl, a downstream metabolite. We also
discovered a cryptic allosteric site for inhibiting the enzyme. Briefly, the feedback inhibitor UDP-Xylose
competes with substrate for the active site; upon binding, UDP-Xyl induces the enzyme to slowly isomerize into
an inactive complex called E. The allosteric transition converts the active site into two novel allosteric sites
called SBS and NBS. The SBS site is specific for the UDP-Xyl inhibitor, but the NBS site can bind either
UDP-Xyl or the substrate UDP-Glc. We hypothesize that the NBS and SBS allosteric sites cooperatively
stabilize E, and the dual-specificity of the NBS is an important feature that allows the abundant substrate
UDP-Glc to enhance the binding affinity of the less abundant inhibitor UDP-Xyl in the SBS. This hypothesis is
based on our preliminary data that (i) the substrate UDP-Glc can bind to the NBS site and inhibit hUGDH, and
(ii) the inhibitor UDP-Xyl can bind to both the SBS and NBS to inhibit. This hypothesis will be tested by the
following specific aims: 1) we will determine how the NBS and SBS allosteric sites interact to enhance the
allosteric inhibition by UDP-Xyl; 2) we will determine the relationship between a putative low barrier hydrogen
bond (LBHB) and the stability of the NBS and SBS allosteric sites; and 3) we will identify the structural
features that couple the intrinsically disordered C-terminus (ID-tail) of hUGDH to the favorable formation of E.
The research proposed in this application is innovative because it focuses on the allosteric inhibition of hUGDH
as a global mechanism for controlling glucuronidation, and uses our recent discoveries of: (i) the novel NBS
allosteric site; (ii) a putitive low barrier hydrogen bond in the allosteric mechanism; and (iii) the entropic force
generated by the intrinsically disordered C-terminus. Since these features are recent discoveries from my lab,
this research is distinct from previous attempts that tried to control glucuronidation. The expected outcomes of
this work are significant. A detailed description of the allosteric mechanism of hUGDH will serve as a
foundation for the design of a class of allosteric inhibitors that will act as global regulators of glucuronidati...

## Key facts

- **NIH application ID:** 10796694
- **Project number:** 3R01GM114298-06S1
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Zachary Arthur Wood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $7,039
- **Award type:** 3
- **Project period:** 2015-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796694

## Citation

> US National Institutes of Health, RePORTER application 10796694, The role of intrinsic disorder in the allosteric regulation of human UGDH (3R01GM114298-06S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10796694. Licensed CC0.

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