Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
34
pubmed:dateCreated
1994-9-22
pubmed:abstractText
The objective of this study was to elucidate the mechanism by which nitric oxide (NO) inhibits NO synthase. Previous studies revealed that NO inhibits unpurified preparations of NO synthase. In the present study, the mechanism by which NO inhibits purified neuronal NO synthase from rat cerebellum was examined. The rate of L-citrulline formation from L-arginine was non-linear despite the presence of excess substrate and cofactors and was further inhibited by 30% by 200 units/ml superoxide dismutase. In contrast, 30 microM oxyhemoglobin increased NO synthase activity by 2-fold and made the reaction rate linear. These observations were consistent with the hypothesis that enzymatically generated NO inhibits NO synthase activity. Exogenous NO (0.1-10 microM) (but not NO2, nitrite, or nitrate) also inhibited NO synthase, and enzyme inhibition was not competitive with L-arginine. NO synthase inhibition by NO and other heme ligands supports the view that heme is involved in the catalytic activity of NO synthase. Oxyhemoglobin prevented but could not reverse enzyme inhibition by NO. NO synthase inhibition by NO was markedly diminished and reversed, however, by tetrahydrobiopterin (50 microM) or a tetrahydrobiopterin-regenerating system, and the latter made the reaction rate linear. In contrast, NO synthase inhibition by NO was markedly enhanced by heme oxidants (10 microM methylene blue; 3 microM ferricyanide), and these oxidants directly inhibited NO synthase activity. These observations suggest that NO interacts with enzyme-bound ferric heme to inhibit NO synthase activity. In support of this view, NO inhibited enzyme activity in the absence of turnover, when the heme iron is in the ferric state, and this inhibition was reversed by tetrahydrobiopterin. Therefore, the oxidation state of heme iron appears to be one important determinant for the inhibitory action of NO, and tetrahydrobiopterin may increase NO synthase activity by diminishing the inhibitory action of NO.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/5,6,7,8-tetrahydrobiopterin, http://linkedlifedata.com/resource/pubmed/chemical/Amino Acid Oxidoreductases, http://linkedlifedata.com/resource/pubmed/chemical/Arginine, http://linkedlifedata.com/resource/pubmed/chemical/Biopterin, http://linkedlifedata.com/resource/pubmed/chemical/Carbon Monoxide, http://linkedlifedata.com/resource/pubmed/chemical/Citrulline, http://linkedlifedata.com/resource/pubmed/chemical/Cyanides, http://linkedlifedata.com/resource/pubmed/chemical/Heme, http://linkedlifedata.com/resource/pubmed/chemical/NADP, http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide, http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase, http://linkedlifedata.com/resource/pubmed/chemical/Oxidants, http://linkedlifedata.com/resource/pubmed/chemical/Oxyhemoglobins, http://linkedlifedata.com/resource/pubmed/chemical/Sulfhydryl Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Superoxide Dismutase
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
269
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
21644-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide.
pubmed:affiliation
Department of Molecular Pharmacology, UCLA School of Medicine 90024.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't