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2‐Thiouracil is a selective inhibitor of neuronal nitric oxide synthase antagonising tetrahydrobiopterin‐dependent enzyme activation and dimerisation
Author(s) -
Palumbo Anna,
d'Ischia Marco,
Cioffi Fernando A
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)02194-3
Subject(s) - tetrahydrobiopterin , chemistry , pteridine , nitric oxide synthase , nitric oxide , enzyme , allosteric regulation , biochemistry , thiouracil , substrate (aquarium) , pharmacology , stereochemistry , endocrinology , biology , thyroid , ecology , organic chemistry
2‐Thiouracil (TU), an established antithyroid drug and melanoma‐seeker, was found to selectively inhibit neuronal nitric oxide synthase (nNOS) in a competitive manner ( K i =20 μM), being inactive on the other NOS isoforms. The drug apparently interfered with the substrate‐ and tetrahydrobiopterin (BH 4 )‐binding to the enzyme. It caused a 60% inhibition of H 2 O 2 production in the absence of L ‐arginine and BH 4 , and antagonised BH 4 ‐induced dimerisation of nNOS, but did not affect cytochrome c reduction. These results open new perspectives in the understanding of the antithyroid action of TU and provide a new lead structure for the development of selective nNOS inhibitors to elucidate the interdependence of the substrate and pteridine sites and to modulate pathologically aberrant NO formation.