INHIBITION OF AMINOPEPTIDASES BY AMASTATIN AND BESTATIN DERIVATIVES - EFFECT OF INHIBITOR STRUCTURE ON SLOW-BINDING PROCESSES
INHIBITION OF AMINOPEPTIDASES BY AMASTATIN AND BESTATIN DERIVATIVES - EFFECT OF INHIBITOR STRUCTURE ON SLOW-BINDING PROCESSES
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DOI：
10.1021/jm00370a001
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发表时间：
1984-01-01
影响因子：
7.3
通讯作者：
HARBESON, S
中科院分区：
文献类型：
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作者：
RICH, DH;MOON, BJ;HARBESON, S
阿司他丁[[(2S，3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-valyl-L-valyl-L-aspartic酸]和bestatin[(2S，3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine][免疫和抗肿瘤药物]是氨基肽酶M(AP-M)的慢结合竞争性抑制剂，净KI为1.9倍。10-8和4.1倍。10-6M。以猪肾AP-M和亮氨酸氨基肽酶(LAP)为研究对象，考察了两种抑制剂的结构对净KI和慢结合抑制的影响。(2S)-羟基有助于快速形成的碰撞络合物[EI]的稳定。相反，增加抑制剂的肽链长度会产生更有效的抑制剂，这是结合过程较慢的结果。他汀类类似物[(3S，4S)-Sta-Val-Val-Asp]刺激而不是抑制LAP。AP-M与三肽和四肽抑制剂的结合比二肽抑制剂更强；LAP与二肽抑制剂的结合更强。结合的差异可以用来区分胞质和膜结合的氨基肽酶。
Amastatin [(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-valyl-L-valyl-L-aspartic acid] and bestatin[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine] [immunologic and antineoplastic drugs] are slow-binding, competitive inhibitors of aminopeptidase M (AP-M) with net Ki of 1.9 .times. 10-8 and 4.1 .times. 10-6 M, respectively. The effect of inhibitor structure on net Ki and on slow-binding inhibition was evaluated for analogs of both inhibitors on [porcine kidney] AP-M and leucine aminopeptidase (LAP). The (2S)-hydroxyl group contributes to the stabilization of a collision complex [EI], which is formed rapidly. In contrast, increasing the peptide chain length of the inhibitor produces more potent inhibitors as a consequence of a slower binding process. A statine analog of amastatin [(3S,4S)-Sta-Val-Val-Asp] stimulated rather than inhibited LAP. AP-M binds tri- and tetrapeptide inhibitors more strongly than dipeptide inhibitors; LAP binds dipeptide inhibitors more strongly. The difference in binding can be used to distinguish cytosolic from membrane-bound aminopeptidases.