α-Keto derivatives of amino acids as inhibitors of trypsinogen activation

Abstract

Deaminated analogues of tyrosine, tryptophan, phenylalanine, and glutamic acid were found to possess a significant inhibitory effect on the autocatalytic activation of trypsinogen and also on the activation by enterokinase. The α-keto derivatives of the three aromatic amino acids were the strongest inhibitors in the group, and of these, p-hydroxyphenylpyruvic acid was the most active compound. In its ability to block both types of activation of trypsinogen, p-hydroxyphenylpyruvic acid was superior to γ-guanidinobutyric acid, the most effective inhibitor previously described. The inhibition of enterokinase was noncompetitive for p-hydroxyphenylpyruvic acid and phenylpyruvic acid, but was competitive for indolepyruvic acid. In the autocatalytic reaction all three aromatic keto acids as well as γ-guanidinobutyric acid behaved as noncompetitive inhibitors. At a concentration of 10 −3 M the aromatic amino acids did not interfere with the caseinolytic activity of trypsin, though this concentration was sufficient to markedly inhibit the autocatalytic process. At the same concentration only indolepyruvic acid showed mild inhibition of the tryptic hydrolysis of tosyl-arginine methyl ester, and the kinetics were those of a noncompetitive reaction.