2-Thiouracil is a selective inhibitor of neuronal nitric oxide synthase antagonising tetrahydrobiopterin-dependent enzyme activation and dimerisation

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 muM), being inactive on the other NOS isoforms, The drug apparently interfered with the substrate- and tetrahydrobiopterin (BH4)-binding to the enzyme. It caused a 60% inhibition of H2O2 production in the absence of L-arginine and BH4, and antagonised BH4-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. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.