Kasuya F, Igarashi K, Fukui M
Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Japan.
Biochem Pharmacol. 1996 Nov 22;52(10):1643-6. doi: 10.1016/s0006-2952(96)00563-1.
Molecular characteristics of carboxylic acids were investigated for the ability to inhibit a purified medium chain acyl-CoA synthetase, using hexanoic acid as a substrate. Salicylic acid, 4-methylsalicylic acid, 2-hydroxynaphtoic acid, and 2-hydroxyoctanoic acid, which do not act as substrates for the medium chain acyl-CoA synthetase, were potent as inhibitors. Valproic acid was not an inhibitor. Salicylic acid, 2-hydroxynaphthoic acid, and 2-hydroxyoctanoic acid inhibited the medium chain acyl-CoA synthetase with Ki values of 37, 5.2, and 500 microM, respectively. 4-Methylsalicylic acid was more potent than salicylic acid. The inhibitory carboxylic acids were competitive with respect to hexanoic acid. The distance of the hydroxyl group from the carboxylic acid group of the benzene ring influenced the inhibitory activity. The hydroxyl group on the carbon adjacent to the carboxylic acid group was required for inhibitory activity. In addition, there was a good correlation between the lipophilicity of the carboxylic acids and the Ki values, suggesting that the lipophilicity of the carboxylic acids is a major determinant for inhibition of the medium chain acyl-CoA synthetase.
以己酸为底物，研究了羧酸抑制纯化的中链酰基辅酶A合成酶的分子特性。水杨酸、4-甲基水杨酸、2-羟基萘甲酸和2-羟基辛酸并非中链酰基辅酶A合成酶的底物，但却是强效抑制剂。丙戊酸不是抑制剂。水杨酸、2-羟基萘甲酸和2-羟基辛酸对中链酰基辅酶A合成酶的抑制常数（Ki）值分别为37、5.2和500微摩尔。4-甲基水杨酸比水杨酸的抑制作用更强。抑制性羧酸与己酸存在竞争性。苯环上羟基与羧基的距离影响抑制活性。抑制活性需要羧基相邻碳原子上的羟基。此外，羧酸的亲脂性与抑制常数之间存在良好的相关性，表明羧酸的亲脂性是抑制中链酰基辅酶A合成酶的主要决定因素。
