STEREOCHEMICAL ASPECTS OF PEPTIDE HYDROLYSIS CATALYZED BY SERINE PROTEASES OF THE CHYMOTRYPSIN TYPE
STEREOCHEMICAL ASPECTS OF PEPTIDE HYDROLYSIS CATALYZED BY SERINE PROTEASES OF THE CHYMOTRYPSIN TYPE
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DOI：
10.1016/0045-2068(81)90042-0
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发表时间：
1981-01-01
影响因子：
5.1
通讯作者：
DUTLER, H
中科院分区：
文献类型：
--
作者：
BIZZOZERO, SA;DUTLER, H
考虑到 Deslongchamps 的立体电子理论，基于现有的广泛结构数据，研究了丝氨酸蛋白酶催化的肽水解的空间过程。这些研究可以阐明中间体的结构，特别是四面体中间体的结构，以及催化过程中发生的主要结构事件。他们揭示了普遍接受的肽水解机制中固有的困难：由于 Ser-195 对羰基碳的亲核攻击而产生的构型中留下的 N 的质子化不能在 His-57 内部发生。讨论了两种与立体电子学理论的所有含义兼容的替代机制。更可能的机制的主要特征是： 构象变化允许 His-57 的咪唑环占据 2 个不同的位置；在一个位置，一个质子从 O.gamma 中被提取出来。 Ser-195 的质子，在另一个中，该质子被捐赠给离开的 N；锥体的构型变化（倒置）使 N 重新定向亲核攻击过程中形成的孤对轨道；在一个方向上允许C.sbd.O键断裂，而在另一个方向上允许C.sbd.N键断裂。该反转过程赋予 N 控制四面体中间体分解的开关特性。
The steric course of peptide hydrolysis catalyzed by serine proteases has been studied on the basis of the available, extensive structural data, taking into account the stereoelectronic theory of Deslongchamps. These studies allowed elucidation of the structure of intermediates, in particular of the tetrahedral intermediate, and of the main structural events taking place during catalysis. They reveal a difficulty inherent in the generally accepted mechanism of peptide hydrolysis: protonation of the leaving N in the configuration arising from nucleophilic attack of Ser-195 on the carbonyl carbon cannot take place internally from His-57. Two alternative mechanisms are discussed which are compatible with all implications of the stereoelectronic theory. The main features of the more probable mechanism are: a conformational change allowing the imidazole ring of His-57 to occupy 2 distinct positions; in one position a proton is abstracted from O.gamma. of Ser-195 and in the other this proton is donated to the leaving N; a configurational change (inversion) of the pyramidal leaving N reorienting the lone-pair orbital developed during nucleophilic attack; in one orientation C.sbd.O bond breaking and in the other C.sbd.N bond breaking is allowed. This inversion process confers on the N the property of a switch controlling the breakdown of the tetrahedral intermediate.