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J Biol Chem, Vol. 275, Issue 18, 13370-13376, May 5, 2000
From the Department of Pharmacology, University of Michigan Medical
School, Ann Arbor, Michigan 48109-0632
It is established that aminoguanidine (AG) is a
metabolism-based inactivator of the three major isoforms of
nitric-oxide synthase. AG is thought to be of potential use in
diseases, such as diabetes, where pathological overproduction of NO is
implicated. We show here that during the inactivation of neuronal
nitric-oxide synthase (nNOS) by AG that the prosthetic heme is altered,
in part, to dissociable and protein-bound adducts. The protein-bound
heme adduct is the result of cross-linking of the heme to residues in
the oxygenase domain of nNOS. The dissociable heme product is unstable
and reverts back to heme upon isolation. The alteration of the heme is
concomitant with the loss in the ability to form the ferrous-CO complex
of nNOS and accounts for at least two-thirds of the activity loss.
Studies with [14C]AG indicate that alteration of
the protein, in part on the reductase domain of nNOS, also occurs but
at low levels. Thus, heme alteration appears to be the major cause of
nNOS inactivation. The elucidation of the mechanism of inactivation of
nNOS will likely lead to a better understanding of the in
vivo effects of NOS inhibitors such as AG.
Aminoguanidine-mediated Inactivation and Alteration of
Neuronal Nitric-oxide Synthase*
,,
*
This work was supported by National Institutes of Health
Grant ES08365 (to Y. O.).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.
Trainee under Pharmacological Sciences Training Program GM07767
from the National Institutes of Health.
§
Recipient of the Burroughs Wellcome Fund New Investigator Award in
Toxicology. To whom correspondence should be addressed: Dept. of
Pharmacology, University of Michigan Medical School, Medical Science
Research Bldg. III, Ann Arbor, MI 48109-0632. Tel.: 734-936-5797; Fax:
734-763-4450; E-mail: osawa@umich.edu.
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