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J. Biol. Chem., Vol. 276, Issue 43, 39872-39878, October 26, 2001
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From the Mutations in copper,zinc-superoxide dismutase
(SOD) have been implicated in familial amyotrophic lateral sclerosis
(FALS). We have investigated the breakdown of
S-nitrosothiols by wild-type (WT) SOD and two common
FALS mutants, alanine-4 valine (A4V) SOD and glycine-37 arginine (G37R)
SOD. In the presence of glutathione, A4V SOD and G37R SOD catalyzed
S-nitrosoglutathione breakdown three times more efficiently
than WT SOD. Indeed, A4V SOD catabolized GSNO more efficiently than WT
SOD throughout the physiological range of GSH concentrations. Moreover,
a variety of additional S-nitrosothiols were catabolized
more readily by A4V SOD than by WT SOD. Initial rate data for fully
reduced WT SOD and A4V SOD, and data using ascorbic acid as the
reductant, suggest that FALS mutations in SOD may influence the
efficiency of reduction of the copper center by glutathione. We have
identified a potentially toxic gain of function of two common FALS
mutations that may contribute to neurodegeneration in FALS.
Accelerated S-Nitrosothiol Breakdown by Amyotrophic
Lateral Sclerosis Mutant Copper,Zinc-Superoxide Dismutase*
,,
**
Department of Chemistry, University of
Virginia, Charlottesville, Virginia 22904, the § Department
of Medicine, University of Massachusetts Medical School, Rose Reed
Gordon Building, Shrewsbury, Massachusetts 01545, the ¶ Department
of Health Evaluation Sciences, Division of Biostatistics and
Epidemiology, University of Virginia Health System, Charlottesville,
Virginia 22908, and the Department of Pediatrics, Division of
Pulmonary Medicine, University of Virginia Health System,
Charlottesville, Virginia 22908
*
This work was supported by the National Institutes of Health
Grants NS34678 (to T. L. M.) and HL59337 (to B. G.).
Additional support was provided by the Henry B. Wallace Foundation and
the University of Virginia Children's Medical Center (to B. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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