Characterization of triacsin C inhibition of short-, medium-, and long-chain fatty acid:CoA ligases of human liver

被引:23
|
作者
Vessey, DA [1 ]
Kelley, M
Warren, RS
机构
[1] Dept Vet Affairs Med Ctr, Inst Liver Studies, San Francisco, CA 94121 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA
关键词
Acyl-CoA synthetase; fatty Acid : CoA ligase; triacsin C;
D O I
10.1002/jbt.20009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Short-, medium-, and long-chain fatty acid:CoA ligases from human liver were tested for their sensitivity to inhibition by triacsin C. The shortchain fatty acid:CoA ligase was inhibited less than 10% by concentrations of triacsin C as high as 80 muM. The two mitochondrial xenobiotic/medium-chain fatty acid:CoA ligases (XM-ligases), HXM-A and HXM-B, were partially inhibited by triacsin C, and the inhibitions were characterized by low affinity for triacsin C (K-I values > 100 muM). These inhibitions were found to be the result of triacsin C competing with medium-chain fatty acid for binding at the active site. The microsomal and mitochondrial forms of long-chain fatty acid:CoA ligase (also termed long-chain fatty acyl-CoA synthetase, or long-chain acyl-CoA synthetase LACS) were potently inhibited by triacsin C, and the inhibition had identical characteristics for both LACS forms. Dixon plots of this inhibition were biphasic. There is a high-affinity site with a K-I of 0.1 muM that accounts for a maximum of 70% of the inhibition. There is also a low affinity site with a K-I of 6 muM that accounts for a maximum of 30% inhibition. Kinetic analysis revealed that the high-affinity inhibition of the mitochondrial and microsomal LACS forms is the result of triacsin C binding at the palmitate substrate site. The high-affinity triacsin C inhibition of both the mitochondrial and microsomal LACS forms was found to require a high concentration of free Mg2+, with the EC50 for inhibition being 3 mM free Mg2+. The low affinity triacsin C inhibition was also enhanced by Mg2+. The data suggests that Mg2+ promotes triacsin C inhibition of LACS by enhancing binding at the palmitate binding site. In contrast, the partial inhibition of the XM-ligases by triacsin C, which showed only a low-affinity component, did not require Mg2+. (C) 2004 Wiley Periodicals, Inc.
引用
收藏
页码:100 / 106
页数:7
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