Agostinis P, Vandenbogaerde A, Donella-Deana A, Pinna L A, Lee K T, Goris J, Merlevede W, Vandenheede J R, De Witte P
Afdeling Biochemie, Faculteit der Geneeskunde, Katholieke Universiteit Leuven, Belgium.
Biochem Pharmacol. 1995 May 26;49(11):1615-22. doi: 10.1016/0006-2952(95)00097-j.
The naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.
萘并二蒽酮金丝桃素可引起对生长因子信号通路中涉及的蛋白激酶的光敏抑制。纳摩尔浓度的金丝桃素可抑制表皮生长因子受体和胰岛素受体的蛋白酪氨酸激酶活性（PTK），而对胞质蛋白酪氨酸激酶Lyn、Fgr、TPK-IIB和CSK无效。金丝桃素的光敏抑制作用并不局限于受体PTK，因为丝氨酸/苏氨酸蛋白激酶（蛋白激酶CK-2、蛋白激酶C和丝裂原活化激酶）也对抑制极其敏感（蛋白激酶CK-2的IC50值 = 6 nM）。对金丝桃素介导的表皮生长因子受体PTK和蛋白激酶CK-2抑制作用的比较表明，这种抑制是不可逆的，严格依赖于用荧光照射酶-抑制剂复合物，并且可能是由自由基中间体的形成介导的（I型机制）。尽管金丝桃素对酶抑制的选择性的确切分子基础仍然未知，但我们的结果表明，远缘相关的蛋白激酶仍可能共享与金丝桃素相互作用的共同反应域。
