Induction of lipid-protein mismatch by xenobiotics: kinetic cooperativity.
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
H
GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institut für Biochemische Pflanzenpathologie, Oberschleissheim, Germany.
Pflugmacher
D
D
D000438:Alcohols / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D019791:Guanidine; D006146:Guanidines / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D009004:Monosaccharide Transport Proteins; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012492:Salts / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D012997:Solvents / Q000494:pharmacology*; D027981:Symporters; D015262:Xenobiotics / Q000494:pharmacology*
D000438:Alcohols; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006146:Guanidines; C050221:LacY protein, E coli; D008563:Membrane Lipids; D008565:Membrane Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D012492:Salts; D012997:Solvents; D027981:Symporters; D015262:Xenobiotics; C021499:lactose permease; D008156:Luciferases; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D019791:Guanidine