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Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase
Biochemistry ( IF 2.9 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.biochem.7b00999
Bradley R. Miller 1 , Yan Kung 1
Affiliation  

The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme’s cofactor preferences. Our structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved. In addition, our structure of HMG-CoA-bound SpHMGR reveals large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle. Taken together, this work provides critical new insights into both the HMGR reaction mechanism and the structural basis of cofactor specificity.

中文翻译:

II类HMG-CoA还原酶中结构底物和结构域运动控制底物结合和辅因子特异性

关键的甲羟戊酸途径酶3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶(HMGR)使用辅因子NAD(P)H还原HMG-CoA,使其在无数代谢产物和天然产物的生产中成为甲羟戊酸。尽管他汀类药物对HMGR的抑制作用是众所周知的,但HMGR催化的一些机理细节仍未解决,并且来自不同生物体的HMGR中NADH或NADPH的广泛辅因子特异性的结构基础也是未知的。在这里,我们介绍了来自肺炎链球菌的HMGR的晶体结构(SpHMGR)以及辅酶偏好的动力学数据。我们的SpHMGR结构与其动力学上首选的NADPH辅因子结合在一起,表明了NADPH特异性结合和识别是如何实现的。另外,我们与HMG-CoA结合的SpHMGR的结构揭示了以前未知的大分子构象结构域运动,该结构域运动可控制HMGR底物结合并实现辅因子交换而在催化循环中无中间释放。两者合计,这项工作为HMGR反应机制和辅因子特异性的结构基础提供了重要的新见解。
更新日期:2017-12-21
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