INHIBITION OF A MEDIUM-CHAIN ACYL-COA SYNTHETASE INVOLVED IN GLYCINE CONJUGATION BY CARBOXYLIC-ACIDS

Molecular characteristics of carboxylic acids were investigated for th e ability to inhibit a purified medium chain acyl-CoA synthetase, usin g hexanoic acid as a substrate. Salicylic acid, 4-methylsalicylic acid , 2-hydroxynaphthoic acid, and 2-hydroxyoctanoic acid, which do not ac t as substrates for the medium chain acyl-CoA synthetase, were potent as inhibitors. Valproic acid was not an inhibitor. Salicylic acid, 2-h ydroxynaphthoic acid, and 2-hydroxyoctanoic acid inhibited the medium chain acyl-CoA synthetase with K-i values of 37, 5.2, and 500 mu M, re spectively. 4-Methylsalicylic acid was more potent than salicylic acid . The inhibitory carboxylic acids were competitive with respect to hex anoic acid. The distance of the hydroxyl group from the carboxylic aci d group of the benzene ring influenced the inhibitory activity. The hy droxyl group on the carbon adjacent to the carboxylic acid group was r equired for inhibitory activity. In addition, there was a good correla tion between the lipophilicity of the carboxylic acids and the K-i val ues, suggesting that the lipophilicity of the carboxylic acids is a ma jor determinant for inhibition of the medium chain acyl-CoA synthetase . Copyright (C) 1996 Elsevier Science Inc.