Rich D H, Moon B J, Harbeson S
J Med Chem. 1984 Apr;27(4):417-22. doi: 10.1021/jm00370a001.
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] are slow-binding, competitive inhibitors of aminopeptidase M (AP-M) with net inhibition constants (Ki) of 1.9 X 10(-8) and 4.1 X 10(-6) M, respectively. The effect of inhibitor structure on net Ki and on slow-binding inhibition was evaluated for analogues of both inhibitors on 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 analogue 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, whereas LAP binds dipeptide inhibitors more strongly. The difference in binding can be used to distinguish cytosolic from membrane-bound aminopeptidases.
氨肽酶抑制剂[(2S,3R)-3-氨基-2-羟基-5-甲基己酰基-L-缬氨酰-L-缬氨酰-L-天冬氨酸]和贝他定[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基-L-亮氨酸]是氨基肽酶M（AP-M）的慢结合竞争性抑制剂，其净抑制常数（Ki）分别为1.9×10⁻⁸和4.1×10⁻⁶M。研究了这两种抑制剂类似物对AP-M和亮氨酸氨肽酶（LAP）的抑制剂结构对净Ki和慢结合抑制的影响。(2S)-羟基有助于快速形成的碰撞复合物[EI]的稳定。相反，由于结合过程较慢，增加抑制剂的肽链长度会产生更强效的抑制剂。氨肽酶抑制剂的一种他汀类似物[(3S,4S)-Sta-Val-Val-Asp]刺激而非抑制LAP。AP-M与三肽和四肽抑制剂的结合比二肽抑制剂更强，而LAP与二肽抑制剂的结合更强。这种结合差异可用于区分胞质氨基肽酶和膜结合氨基肽酶。
