Structural insight into substrate and product binding in an archaeal mevalonate kinase
Structural insight into substrate and product binding in an archaeal mevalonate kinase
复制标题
DOI：
10.1371/journal.pone.0208419
复制
发表时间：
2018-12-06
期刊：
影响因子：
3.7
通讯作者：
Kung, Yan
中科院分区：
文献类型：
--
作者：
Miller, Bradley R.;Kung, Yan
甲羟戊酸激酶（MK）是甲羟戊酸途径的关键酶，其产生类固醇（包括胆固醇）和类异戊二烯（最大类的天然产物）的生物合成前体。目前可获得的晶体结构的MK从不同的生物体描绘的酶在其未结合的，底物结合的，和底物结合的形式，然而，到目前为止，没有结构尚未确定的MK结合到其产品，5-磷酸甲羟戊酸。在这里，我们提出了甲羟戊酸结合和5-磷酸甲羟戊酸结合的甲烷八叠球菌（MmMK），产甲烷古菌的MK的晶体结构。与甲羟戊酸结合的真核MK的先前结构相反，我们发现这种古细菌MK与其底物之间明显缺乏直接相互作用。此外，这两个MmMK结构加入了脱辅基酶的先前结构，以完成描绘相同MK的未结合、底物结合和产物结合形式的第一套结构快照。有了这些结构的集合，我们现在对这种生物必需酶的催化机制提供了更多的见解。
Mevalonate kinase (MK) is a key enzyme of the mevalonate pathway, which produces the biosynthetic precursors for steroids, including cholesterol, and isoprenoids, the largest class of natural products. Currently available crystal structures of MK from different organisms depict the enzyme in its unbound, substrate-bound, and inhibitor-bound forms; however, until now no structure has yet been determined of MK bound to its product, 5-phosphomevalonate. Here, we present crystal structures of mevalonate-bound and 5-phosphomevalonate-bound MK from Methanosarcina mazei (MmMK), a methanogenic archaeon. In contrast to the prior structure of a eukaryotic MK bound with mevalonate, we find a striking lack of direct interactions between this archaeal MK and its substrate. Further, these two MmMK structures join the prior structure of the apoenzyme to complete the first suite of structural snapshots that depict unbound, substrate-bound, and product-bound forms of the same MK. With this collection of structures, we now provide additional insight into the catalytic mechanism of this biologically essential enzyme.