Abstract
Homotropic cooperativity in Drosophila melanogaster acetylcholinesterase seems to be a consequence of an initial substrate binding to a high-affinity peripheral substrate binding site situated around the negative charge of D413 (G335, Torpedo numbering). An appropriate mutation which turns the peripheral binding site to a low-affinity spot abolishes apparent activation but improves the overall enzyme effectiveness. This contradiction can be explained as less effective inhibition due to a shorter occupation of such a peripheral site. A similar effect can be achieved by an appropriate peripheral inhibitor such as TC, which can in special cases, when less effective heterotropic inhibition prevails over homotropic, acts as an activator. At the highest substrate concentrations, however, these enzymes are always inhibited, although steric components may influence the strength of inhibition like in the F368G mutant (F290, Torpedo numbering). Cooperative effects thus may include a steric component, but covering of the entrance must affect influx and efflux to different extents.
