Palumbo A, d'Ischia M, Cioffi F A
Zoological Station Anton Dohrn, Naples, Italy.
FEBS Lett. 2000 Nov 24;485(2-3):109-12. doi: 10.1016/s0014-5793(00)02194-3.
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.
2-硫尿嘧啶（TU）是一种已确立的抗甲状腺药物和黑色素瘤导向剂，被发现以竞争性方式（K(i)=20微摩尔）选择性抑制神经元型一氧化氮合酶（nNOS），对其他一氧化氮合酶同工型无活性。该药物明显干扰底物和四氢生物蝶呤（BH(4)）与酶的结合。在没有L-精氨酸和BH(4)的情况下，它导致H(2)O(2)产生抑制60%，并拮抗BH(4)诱导的nNOS二聚化，但不影响细胞色素c还原。这些结果为理解TU的抗甲状腺作用开辟了新的视角，并为开发选择性nNOS抑制剂提供了新的先导结构，以阐明底物和蝶啶位点的相互依赖性，并调节病理性异常的一氧化氮形成。
