Inhibitors can activate proteases to catalyze the synthesis and hydrolysis of peptides.
Competitive inhibitors can activate proteases (papain, trypsin, and cathepsin S) to catalyze the synthesis of peptide bonds and accelerate the hydrolysis of poor substrates (from 1 to 99%). Reaction mixtures contained intermediate molecules that were formed by the coupling of the inhibitor with the poor substrate. This and other findings suggest the following chain of events. Part of the binding energy of formation of the enzyme-inhibitor complex was used to activate the inhibitor, i.e., to form acyl-enzyme species with a high-energy bond (e.g., a thioester bond in the case of papain) required for coupling the inhibitor with the substrate to form the intermediate molecule. The latter was subjected to successive reactions which led to a stepwise degradation of the substrate, as well as to the regeneration of the inhibitor. One mole of the inhibitor could catalyze rapid hydrolysis of at least 53 mol of substrate. The intermediate molecules were the species undergoing rapid hydrolysis. Therefore, 1 mol of inhibitor was involved in the synthesis of 53 mol of intermediate molecules; i.e., the inhibitor functioned as a cofactor that catalyzed the synthesis of peptides. Thus, the binding energy of formation of the enzyme-inhibitor complex can be utilized to catalyze the synthesis of peptide bonds in the absence of an exogenous energy source (e.g., ATP).
Schechter
Israel
I
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. israel.schechter@weizmann.ac.il
Ziv
Etty
E
D001667:Binding, Competitive; D004151:Dipeptides / Q000378:metabolism; D004789:Enzyme Activation; D006868:Hydrolysis; D007700:Kinetics; D010206:Papain / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism
D004151:Dipeptides; D010455:Peptides; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D014357:Trypsin; D010206:Papain