Modes of inhibition by acylcarnitines, adriamycin and trifluoperazine of cardiac phospholipid-sensitive calcium-dependent protein kinase.
Modes of inhibition by acylcarnitines, adriamycin and trifluoperazine of cardiac phospholipid-sensitive calcium-dependent protein kinase.
复制标题
酰基肉碱、阿霉素和三氟拉嗪对心脏磷脂敏感的钙依赖性蛋白激酶的抑制模式。
DOI：
10.1016/0006-2952(83)90280-0
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发表时间：
1983
影响因子：
5.8
通讯作者：
Kuo,JF
中科院分区：
文献类型：
--
作者：
Wise,BC;Kuo,JF
棕榈酰卡尼汀、阿霉素和三氟拉嗪对磷脂辅助因子磷脂酰丝氨酸、纯化的磷脂敏感的Ca2t̄依赖的蛋白激酶具有竞争性抑制作用，其Ki值分别为3、49和14、14μM。这些化合物对金属激活剂Ca−也有竞争性抑制作用，其Ki值分别为0.8、14 0和9，μM。棕榈酰卡尼汀和三氟拉嗪合用对酶有协同抑制作用。另一方面，棕榈酰肉碱和阿霉素的结合表现出简单的加成抑制作用。或三氟拉嗪和阿霉素。1，3-二油酸甘油酯通过增加酶对磷脂酰丝氨酸的亲和力而降低三氟拉嗪的抑制作用。结果表明，最近发现的磷脂敏感的钙−依赖的蛋白激酶物种被多种试剂抑制，可能是因为它们能够干扰磷脂和酶之间的疏水相互作用，这种相互作用可能需要赋予酶钙−敏感性，因为其他长链脂肪酰肉碱(硬脂酰肉碱和亚油酰肉碱)、短链硬脂酰肉碱(如辛酰肉碱)和棕榈酰辅酶A。与棕榈酰肉碱相比，它们作为抑制剂的活性较低，进一步表明亲脂性以及其他结构决定因素对化合物调节酶活性的能力至关重要。
Palmitoylcarnitine, adriamycin, and trifluoperazine competively inhibited, with respect to phosphatidylserine (a phospholipid cofactor), purified cardiac phospholipid-sensitive Ca2t̄-dependent protein kinase, with apparentKivalues of 3, 49 and 14, 14μM respectively. These compounds also inhibited the enzyme competitively with respect to Ca−(a metal activator), with corresponding apparentKivalues of 0.8, 140 and 9, μM. A synergistic inhibition was observed when palmitoylcarnitine and trifluoperazine were present in combination. A simple addition inhibition, on the other hand, was observed for the combination of either palmitoylcarnitine and adriamycin. or trifluoperazine and adriamycin. 1,3-Diolein decreased the inhibitory effect of trifluoperazine by increasing the affinity of the enzyme for phosphatidylserine. The results indicate that the recently identified phospholipid-sensitive species of Ca2−-dependent protein kinase was inhibited by a variety of agents, probably via their abilities to interfere with a hydrophobic interaction between phospholipid and the enzyme, an interaction presumably required to confer upon the enzyme a Ca2−sensitivity, Because other long-chain fatty acylcarnitines (stearoyl- and linoleoylcarnitine), short-chain tatty acylcarnitines (such as octanoylcarnitine) and palmitoyl CoA. compared to palmitoylcarnitine, were less active as inhibitors, it is further suggested that lipophilicitv as well as other structural determinants are crucial for the ability of compounds to regulate the enzyme activity.