Lipophilic inhibitors such as general anaesthetics or drugs can conceivably act by displacing boundary lipid molecules that are required by many functional membrane proteins. The resulting lipid-protein mismatch has been analyzed previously in terms of multiple site kinetics (Sandermann, H. (1993) Biochim. Biophys. Acta 1150, 130-133). Expressions for kinetic cooperativity are now derived, and data for the inhibition of dog kidney Na+,K+-ATPase and Escherichia coli lactose permease by organic solvents are presented and analyzed. Half-maximal inhibitor concentrations were without diagnostic value because they were within the general range of critical solvent concentrations known for general anaesthesia and several membraneous and non-membraneous systems, as well as two specific liposomal parameters. The kinetic cooperativity of inhibition was of much higher diagnostic value because the cooperativity Values for the solvent inhibition of Na+,K+-ATPase and lactose permease were characteristic for the lipid displacement mechanism, in contrast to cooperativity values of protein kinase C and luciferase. The latter enzymes are known not to require a boundary lipid layer, so that the degree of kinetic cooperativity provides a new diagnostic tool to distinguish between modes of action of lipophilic inhibitors.
Sandermann, H., & Pflugmacher, D. (1996). Induction of lipid-protein mismatch by xenobiotics: Kinetic cooperativity. Biochimica et Biophysica Acta - Lipids and Lipid Metabolism, 1300(3), 219–225. https://doi.org/10.1016/0005-2760(96)00017-3