Mechanism of inhibition of pepsin by pepstatin. Effect of inhibitor structure on dissociation constant and time-dependent inhibition.
Mechanism of inhibition of pepsin by pepstatin. Effect of inhibitor structure on dissociation constant and time-dependent inhibition.
复制标题
DOI：
10.1016/0006-2952(80)90199-9
复制
发表时间：
1980-08
影响因子：
5.8
通讯作者：
D. Rich;E. Sun
中科院分区：
文献类型：
--
作者：
D. Rich;E. Sun
本文研究了胃蛋白酶抑制剂及其九种合成类似物对胃蛋白酶的抑制作用。进展曲线数据的分析表明，胃酶抑素（1）产生的抑制作用符合一种机制，即快速形成的酶-抑制剂复合物（碰撞复合物）缓慢转化为更紧密结合的复合物（收紧复合物）。本文报道了胃蛋白酶抑制剂和九种胃蛋白酶抑制剂类似物的碰撞复合物的解离常数k2/k1和形成（k3）和逆转（k4）的一级速率常数。数据显示，至少需要三个结构参数来诱导胃蛋白酶抑制素对胃蛋白酶的紧密结合抑制的滞后瞬态特征。这些是：胃酶抑制素的第三个残基中的3（S）-羟基，第一个残基中的异丙基或其等同物，和C-末端二肽基的一部分-Ala-Sta。这些数据表明，这些群体相互作用的合作，以诱导抑制的时间依赖性增加。去除这些结合基团的任何影响，主要是，K4，一阶速率常数返回收紧复杂的碰撞复杂。胃蛋白酶抑制素是胃蛋白酶催化水解酰胺键的过渡态的模拟物的建议进行了讨论。
Investigations were made of the inhibition of pepsin by pepstatin and nine synthetic analogs of pepstatin. Analysis of progress curve data indicated that the inhibition produced by pepstatin (1) conforms to a mechanism in which a rapidly formed enzyme-inhibitor complex (collision complex) is transformed slowly to a more tightly bound complex (tightened complex). Dissociation constants for the collision complexk2/k1and first-order rate constants for formation (k3) and reversal (k4) of the tightened complex are reported for pepstatin and nine pepstatin analogs. The data show that at least three structural parameters are needed to induce the lag transient characteristic of the tight-binding inhibition of pepsin by pepstatin. These are: a 3(S)-hydroxyl group in the third residue of pepstatin, an isopropyl group or its equivalent in the first residue, and some portion of the C-terminal dipeptidyl group -Ala-Sta. The data indicate that these groups interacted cooperatively to induce the timedependent increase in inhibition. Removal of any of these binding groups affected, predominatly,k4, the first-order rate constant for return of tightened complex to collision complex. The proposal that pepstatin is an analog of the transition state for pepsin catalyzed hydrolysis of amide bonds is discussed.