Differentiating serine and cysteine protease mechanisms by new covalent QSAR descriptors.
Differentiating serine and cysteine protease mechanisms by new covalent QSAR descriptors.
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通过新的共价 QSAR 描述符区分丝氨酸和半胱氨酸蛋白酶机制。
DOI：
10.1002/cbic.201000459
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Albeck,Amnon
中科院分区：
文献类型：
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作者：
Shokhen,Michael;Traube,Tamar;Vijayakumar,Subramaniam;Hirsch,Michal;Uritsky,Neta;Albeck,Amnon
在丝氨酸蛋白酶的第一个催化步骤中，攻击性Ser亲核试剂与底物的羰基形成不稳定的共价阴离子四面体复合物TC（O-）（图1a）。[1]在反应配位类似物抑制剂（RCA）[2]的情况下，在形成新的O-C共价键时释放的能量足以使TC（O-）作为终产物的热力学稳定，[3]例如α-酮杂环抑制剂。[4]Cys蛋白酶的催化机制仍在争论中。[5]Cys的硫醇盐阴离子比Ser的羟基阴离子亲核性弱得多。[6]因此，RCA抑制剂在半胱氨酸蛋白酶中的结合可能需要TC的进一步稳定，这可以通过其质子化和中性TC（OH）的形成来实现（图11）。
In the first catalytic step in serine proteases, the attacking Ser nucleophile forms an unstable covalent anionic tetrahedral complex, TC (O-), with the carbonyl group of the substrate (Fig. 1a).[1] In the case of reaction coordinate analog inhibitors (RCA)[2] the energy released in the formation of the new O—C covalent bond is sufficient for the thermodynamic stabilization of TC (O-) as the end products,[3] as for instance with α-ketoheterocycle inhibitors.[4] The catalytic mechanism of Cys proteases is still under debate.[5] The thiolate anion of Cys is much weaker nucleophile than the hydroxyl anion of Ser.[6] Therefore, the binding of RCA inhibitors in cysteine proteases may require further stabilization of TC, which could be realized by its protonation and the formation of a neutral TC (OH)(Fig.