The inhibition patterns of several inhibitors of acetylcholinesterase were studied during the steady-state hydrolysis of three acetic acid esters. The competitive and uncompetitive inhibition constants were tabulated. Data on competitive inhibition are consistent with the assumption that all three acetic acid ester substrates and a dimethyl-carbamic acid ester substrate are hydrolyzed at the same enzyme active site. Certain pairs of compounds appeared to bind simultaneously to the enzyme in a ternary complex, and such pairs acting in concert inhibited acetylcholine hydrolysis to an extent many times greater than that observed for either compound alone. A formal model of enzyme catalysis is proposed to account for these synergistic effects, and detailed examination of the inhibition data test the predictions of specific molecular interactions within the model. Compounds which act synergistically show evidence of simultaneously interacting with two regions of the active site; these regions are proposed to become separated as a result of a conformational change of the enzyme. A potential role for this conformational change in the cholinergic receptor mechanism of excitable membranes is discussed.
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