人HMG-CoA还原酶催化部分的晶体结构：对活性调节和催化作用的见解。
Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
作者信息
Istvan E S, Palnitkar M, Buchanan S K, Deisenhofer J
机构信息
Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, TX 75235-9050, USA.
出版信息
EMBO J. 2000 Mar 1;19(5):819-30. doi: 10.1093/emboj/19.5.819.
Abstract
3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoids. The activity of HMGR is controlled through synthesis, degradation and phosphorylation to maintain the concentration of mevalonate-derived products. In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high serum cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP(+), provide a detailed view of the enzyme active site. Catalytic portions of human HMGR form tight tetramers. The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why binding of HMGR inhibitors to bacterial HMGRs has not been reported.
摘要
3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）催化甲羟戊酸的形成，这是甾醇和类异戊二烯生物合成中的关键步骤。HMGR的活性通过合成、降解和磷酸化来控制，以维持甲羟戊酸衍生产物的浓度。除了对HMGR的生理调节外，人类的这种酶已成为临床上治疗高血清胆固醇水平药物的成功靶点。人HMGR催化部分与HMG-CoA、与HMG和CoA以及与HMG、CoA和NADP(+)形成复合物的三种晶体结构，提供了该酶活性位点的详细视图。人HMGR的催化部分形成紧密的四聚体。晶体结构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。人HMGR的活性位点结构与细菌HMGR不同；这可能解释了为何尚未有关于HMGR抑制剂与细菌HMGR结合的报道。
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