# MECHANISTIC STUDIES OF XANTHINE OXIDASE

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 1989 · $126,983

## Abstract

A comprehensive mechanistic study of the molybdoflavoenzyme
xanthine oxidase is proposed focusing on two central aspects of the
catalytic behavior of this important enzyme, which catalyzes the
final two steps in purine catabolism.  In the first aspect of the
proposed work, the reductive half-reaction of the catalytic cycle
will be comprehensively examined with the aim of establishing the
detailed chemistry that occurs in the conversion of xanthine to
uric acid.  The results will be interpreted in terms of a specific
chemical mechanisms proposed for the reductive half-reaction.
The structure of the complex of alloxanthine with xanthine oxidase
will specifically be examined in this aspect of the proposed work.
This complex is thought to be a particularly stable analog to a
specific catalytic intermediate, and is also of clinical significance
in that its great stability is the basis for the remarkable clinical
efficacy of allopurinol.  This well-tolerated drug is used in the
treatment of hyperuricemia associated with such diverse
conditions as gout and gouty arthritis, and enzyme deficiencies in
hypoxanthine-guanine phosphoribosyltransferase (Lesch-Nyhan
syndrome) and glucose-6-phosphatase (von Gierke's disease).  In the
second aspect of the proposed work, the interaction of the four
oxidation-reduction centers in xanthine oxidase will be
quantitatively examined in an effort to determine the rates at
which reducing equivalents equilibrate in the enzyme, and the
extent to which the equilibration of reducing equivalents
influences catalytic turnover.  The presence in xanthine oxidase
of multiple sites capable of reversibly accepting reducing
equivalents offers the opportunity to examine the transfer of
electrons from one biological center to another while being held
at a fixed distance and orientation within a more or less rigid
polypeptide matrix.  This has become an area of great interest in
biophysics, and the careful examination of the properties of
xanthine oxidase is expectd to yield significant information
regarding the principles governing electron transfer in biological
systems.  The mode of interaction of the various centers in
xanthine oxidase may also be relevant in the production of
superoxide by xanthine oxidase.  This too is of clinical
significance given that enzyme-generated superoxide has been
proposed to play a significant role in ischemia-related tissue
damage (in atherosclerosis and heart attack).

## Key facts

- **NIH application ID:** 3158965
- **Project number:** 5R01AR038917-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **SAM.gov UEI:** DLWBSLWAJWR1
- **Principal Investigator:** Russ Hille
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $126,983
- **Award type:** 5
- **Project period:** 1988-04-01 → 1993-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3158965

## Citation

> US National Institutes of Health, RePORTER application 3158965, MECHANISTIC STUDIES OF XANTHINE OXIDASE (5R01AR038917-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3158965. Licensed CC0.

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