Tomoda H, Igarashi K, Cyong J C, Omura S
Research Center for Biological Function, Kitasato Institute, Tokyo, Japan.
J Biol Chem. 1991 Mar 5;266(7):4214-9.
Triacsins A, B, C, and D are new inhibitors of long chain acyl-CoA synthetase (EC 6.2.1.3) and possess different inhibitory potencies against the enzyme (Tomoda, H., Igarashi, K., and Omura, S. (1987) Biochim. Biophys. Acta 921, 595-598). Acyl-CoA synthetase activity in the membrane fraction of Raji cells was also inhibited by triacsins. The same hierarchy of inhibitory potency as that against the enzyme from other sources, triacsin C greater than triacsin A much greater than triacsin D greater than or equal to triacsin B, was observed. When Raji cells were cultivated in the presence of triacsins, cell proliferation was inhibited in a dose-dependent fashion. The drug concentrations required for 50% inhibition of cell growth at day 2 were calculated to be 1.8 microM for triacsin A, much greater than 20 microM for triacsin B, 1.0 microM for triacsin C, and much greater than 15 microM for triacsin D, demonstrating a hierarchy for inhibitory potency of triacsins similar to that against the acyl-CoA synthetase activity. To understand the role of long chain acyl-CoA synthetase in animal cells, the effect of triacsins on the lipid metabolism of Raji cells was studied. When intact Raji cells were incubated with [14C]oleate in the presence of individual triacsins, the incorporation of [14C]oleate into each of the lipid fractions such as phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol was inhibited to an analogous extent. A common hierarchy, triacsin C greater than triacsin A much greater than triacsin D greater than triacsin B, was shown for the inhibition in each synthesis of the three lipids, which was identical with that for acyl-CoA synthetase. These findings indicate that the inhibition of acyl-CoA synthetase is well correlated with the inhibition of lipid synthesis. Taken together, the data strongly suggest that the inhibition of acyl-CoA synthetase by triacsins leads to the inhibition of lipid synthesis and eventually to the inhibition of proliferation of Raji cells.
曲菌素A、B、C和D是长链脂酰辅酶A合成酶（EC 6.2.1.3）的新型抑制剂，对该酶具有不同的抑制效力（友田博、五十岚健、大村智（1987年），《生物化学与生物物理学报》921卷，595 - 598页）。曲菌素也能抑制Raji细胞膜组分中的脂酰辅酶A合成酶活性。观察到其抑制效力的等级与对其他来源酶的抑制效力等级相同，即曲菌素C大于曲菌素A远大于曲菌素D大于或等于曲菌素B。当Raji细胞在曲菌素存在的情况下培养时，细胞增殖受到剂量依赖性抑制。计算得出在第2天抑制50%细胞生长所需的药物浓度，曲菌素A为1.8微摩尔，曲菌素B远大于20微摩尔，曲菌素C为1.0微摩尔，曲菌素D远大于15微摩尔，这表明曲菌素的抑制效力等级与对脂酰辅酶A合成酶活性的抑制效力等级相似。为了解长链脂酰辅酶A合成酶在动物细胞中的作用，研究了曲菌素对Raji细胞脂质代谢的影响。当完整的Raji细胞在单个曲菌素存在的情况下与[14C]油酸一起孵育时，[14C]油酸掺入磷脂酰胆碱、磷脂酰乙醇胺和三酰甘油等各个脂质组分的过程受到类似程度的抑制。在这三种脂质的每种合成过程中的抑制作用呈现出共同的等级，即曲菌素C大于曲菌素A远大于曲菌素D大于曲菌素B，这与脂酰辅酶A合成酶的抑制等级相同。这些发现表明脂酰辅酶A合成酶的抑制与脂质合成的抑制密切相关。综上所述，数据强烈表明曲菌素对脂酰辅酶A合成酶的抑制导致脂质合成的抑制，并最终导致Raji细胞增殖的抑制。
