Inhibition of human pancreatic elastase 2 by peptide chloromethyl ketones.
The inactivation of human pancreatic elastase 2 (EC 3.4.21.11) by a series of peptide chloromethyl ketones has been investigated. Among a series of compounds with the structure X-Ala-Ala-Pro-Y-CH2Cl (where X=acetyl-, succinyl-, methylsuccinyl-, or H-), the kinetic parametrs for inhibition of elastas 2 depend markedly on the amino acid (Y) in the P1 position. Succinyl-Ala-Ala-Pro-Leu-CH2Cl was found to be an extremely effective inhibitor of human elastase 2, qith a first-order rate constant for covalent bond formation (k3) of 0.033s-1 and a dissociation constant, Ki, for the enzyme inhibitor complex of 7.4 . 10(-7) M. The second-order rate constant k3/Ki for inhibition of elastase 2 by the analogous compound containing a free amino group in place of the succinyl moiety is 150 times lower than that found for the succinyl or acetyl derivative, suggesting that the presence of a positive charge at this position reduces the proper binding of the inhibitor to the enzyme.
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D010179:Pancreas / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*
D000590:Amino Acid Chloromethyl Ketones; D010196:Pancreatic Elastase