Istvan E S, Deisenhofer J
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Biochim Biophys Acta. 2000 Dec 15;1529(1-3):9-18. doi: 10.1016/s1388-1981(00)00134-7.
In higher plants, fungi, and animals isoprenoids are derived from the mevalonate pathway. The carboxylic acid mevalonate is formed from acetyl-CoA and acetoacetyl-CoA via the intermediate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). The four-electron reduction of HMG-CoA to mevalonate, which utilizes two molecules of NADPH, is the committed step in the biosynthesis of isoprenoids. This reaction is catalyzed by HMG-CoA reductase (HMGR). The activity of HMGR is controlled through synthesis, degradation and phosphorylation. The human enzyme has also been targeted successfully by drugs, known as statins, in the clinical treatment of high serum cholesterol levels. The crystal structure of the catalytic portion of HMGR has been determined recently with bound reaction substrates and products. The structure illustrates how HMG-CoA and NADPH are recognized and suggests a catalytic mechanism. Catalytic portions of human HMGR form tight tetramers, explaining the influence of the enzyme's oligomeric state on the activity and suggesting a mechanism for cholesterol sensing.
在高等植物、真菌和动物中，类异戊二烯是由甲羟戊酸途径衍生而来的。羧酸甲羟戊酸是由乙酰辅酶A和乙酰乙酰辅酶A通过中间体3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）形成的。HMG-CoA利用两分子的NADPH进行四电子还原生成甲羟戊酸，这是类异戊二烯生物合成中的关键步骤。该反应由HMG-CoA还原酶（HMGR）催化。HMGR的活性通过合成、降解和磷酸化来控制。在高血清胆固醇水平的临床治疗中，人类的这种酶也已被称为他汀类药物的药物成功靶向。最近已经确定了结合反应底物和产物的HMGR催化部分的晶体结构。该结构说明了HMG-CoA和NADPH是如何被识别的，并提出了一种催化机制。人类HMGR的催化部分形成紧密的四聚体，这解释了酶的寡聚状态对活性的影响，并提出了一种胆固醇传感机制。
