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 microM), 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.
Palumbo
A
A
Zoological Station Anton Dohrn, Naples, Italy. palumbo@alpha.szn.it
d'Ischia
M
M
Cioffi
F A
FA
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D001120:Arginine / Q000378:metabolism; D001667:Binding, Competitive; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D002531:Cerebellum / Q000201:enzymology; D002956:Citrulline / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D013889:Thiouracil / Q000494:pharmacology*
D013956:Antithyroid Agents; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D001708:Biopterins; D002956:Citrulline; D013889:Thiouracil; D001120:Arginine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C003402:sapropterin