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

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2023 · $307,172

## Abstract

PROJECT SUMMARY
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 EW. The allosteric transition converts the active site into two novel allosteric sites
called SBSW and NBSW. The SBSW site is specific for the UDP-Xyl inhibitor, but the NBSW site can bind either
UDP-Xyl or the substrate UDP-Glc. We hypothesize that the NBSW and SBSW allosteric sites cooperatively
stabilize EW, and the dual-specificity of the NBSW 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 SBSW. This hypothesis is
based on our preliminary data that (i) the substrate UDP-Glc can bind to the NBSW site and inhibit hUGDH, and
(ii) the inhibitor UDP-Xyl can bind to both the SBSW and NBSW to inhibit. This hypothesis will be tested by the
following specific aims: 1) we will determine how the NBSW and SBSW 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 NBSW and SBSW 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 EW.
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 NBSW
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 glucuronidation.
And more...

## Key facts

- **NIH application ID:** 10709476
- **Project number:** 5R01GM114298-07
- **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:** $307,172
- **Award type:** 5
- **Project period:** 2015-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709476

## Citation

> US National Institutes of Health, RePORTER application 10709476, The role of intrinsic disorder in the allosteric regulation of human UGDH (5R01GM114298-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10709476. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*