Feingold K R, Moser A H
Arch Biochem Biophys. 1986 Aug 15;249(1):46-52. doi: 10.1016/0003-9861(86)90558-8.
Previous studies have demonstrated that the in vitro activation of microsomal hepatic hydroxymethylglutaryl (HMG) CoA reductase by dephosphorylation is inhibited by HMG CoA or NADPH, the substrates of HMG CoA reductase (13). In the present study the effect of three competitive inhibitors of HMG CoA reductase on the activation of HMG CoA reductase was investigated. Adenosine-2'-monophospho-5'-diphosphoribose, a competitive inhibitor for the NADPH binding site, blocked the phosphatase-mediated activation of HMG CoA reductase. By contrast, neither compactin nor mevinolin, competitive inhibitors for the HMG CoA binding site, altered the activation of HMG CoA reductase. Moreover, the HMG CoA-mediated inhibition of the activation of HMG CoA reductase was not blocked even by very high concentrations of either compactin or mevinolin. These observations suggest that HMG CoA can bind to two sites on HMG CoA reductase. One site of HMG CoA binding serves as a catalytic site and is competitively blocked by compactin or mevinolin, and the second binding site is an allosteric site to which only HMG CoA is capable of binding. The binding of HMG CoA to this second site inhibits the activation of HMG CoA reductase by phosphatases.
先前的研究表明，羟甲基戊二酰辅酶A还原酶（HMG CoA还原酶）经去磷酸化作用在体外的激活会受到HMG CoA还原酶的底物HMG CoA或NADPH的抑制（13）。在本研究中，研究了三种HMG CoA还原酶竞争性抑制剂对HMG CoA还原酶激活的影响。腺苷-2'-单磷酸-5'-二磷酸核糖，一种NADPH结合位点的竞争性抑制剂，阻断了磷酸酶介导的HMG CoA还原酶的激活。相比之下，无论是洛伐他汀还是美伐他汀，这两种HMG CoA结合位点的竞争性抑制剂，都未改变HMG CoA还原酶的激活。此外，即使使用非常高浓度的洛伐他汀或美伐他汀，HMG CoA介导的对HMG CoA还原酶激活的抑制作用也未被阻断。这些观察结果表明，HMG CoA可以与HMG CoA还原酶上的两个位点结合。HMG CoA的一个结合位点作为催化位点，可被洛伐他汀或美伐他汀竞争性阻断，而第二个结合位点是一个变构位点，只有HMG CoA能够与之结合。HMG CoA与该第二个位点的结合会抑制磷酸酶对HMG CoA还原酶的激活。
