Faas F H, Carter W J, Wynn J O
Biochim Biophys Acta. 1978 Nov 22;531(2):158-66. doi: 10.1016/0005-2760(78)90139-x.
The influence of the fatty acyl-CoA thioesters on rat liver microsomal hydroxymethylglutaryl-CoA reductase activity was tested in vitro to determine if the previously demonstrated inhibition of [14C]acetate incorporation into cholesterol is due to inhibition of this rate limiting step in cholesterol synthesis. The polyunsaturated fatty acyl-CoA thioesters caused the greatest inhibition of enzyme activity, 50 micron arachidonoyl-CoA inhibiting 67% and 5 micron inhibiting 22%. 50 micron linoleoyl-CoA inhibited 56% with the more saturated thioesters causing less inhibition. 50--100 micron free fatty acids, free CoA, cholesterol esters, phospholipids, carnitine derivatives, prostaglandins and non-specific detergents caused little or no inhibition of enzyme activity. Kinetic studies revealed the inhibition to be noncompetitive with respect to hydroxymethylglutaryl-CoA with a Ki for arachidonoyl CoA of 3.10 micron. Fatty acyl-CoA inhibition of in vitro cholesterol synthesis is due to inhibition of hydroxymethylglutaryl-CoA reductase activity. Variation in intracellular concentrations of fatty acyl-CoA thioesters may signficantly alter cholesterol synthesis.
在体外测试了脂肪酰基辅酶A硫酯对大鼠肝脏微粒体羟甲基戊二酰辅酶A还原酶活性的影响，以确定先前证实的[14C]乙酸掺入胆固醇的抑制作用是否是由于胆固醇合成中这一限速步骤的抑制所致。多不饱和脂肪酰基辅酶A硫酯对酶活性的抑制作用最大，50微摩尔花生四烯酰辅酶A抑制67%，5微摩尔抑制22%。50微摩尔亚油酰辅酶A抑制56%，饱和度更高的硫酯抑制作用较小。50 - 100微摩尔游离脂肪酸、游离辅酶A、胆固醇酯、磷脂、肉碱衍生物、前列腺素和非特异性去污剂对酶活性几乎没有抑制作用。动力学研究表明，这种抑制作用对羟甲基戊二酰辅酶A是非竞争性的，花生四烯酰辅酶A的Ki为3.10微摩尔。脂肪酰基辅酶A对体外胆固醇合成的抑制作用是由于对羟甲基戊二酰辅酶A还原酶活性的抑制。细胞内脂肪酰基辅酶A硫酯浓度的变化可能会显著改变胆固醇的合成。
