Kinetics of monovalent ion activation of the (Na +-K +)-dependent adenosine triphosphatase and a model for ion translocation and its inhibition by the cardiac glycosides

Abstract

General equations relating the activity of the (Na +-K +)-dependent ATPase and of active ion fluxes to the intracellular monovalent ion concentrations have been developed. Solution to these equations indicates that: (1) The hydrolysis of ATP is catalyzed by three monovalent ions. One of the ions is specifically a sodium ion while the other two may be sodium or potassium ions; (2) The ratio of the formation constants of the sodium and potassium ions for their binding sites is between 10.4 and 16.4; (3) The individual intracellular ions catalyzing the ATPase are the ions actively transported to the extracellular solution during ATP hydrolysis. A model of an enzyme-ATP-ion complex having ion specificity by virtue of size-restricted sites is presented to explain statements 1 and 2. The inhibition of the enzyme by the cardiac glycosides is explained on the basis of their spatial similarity to the enzyme-ATP-ion complex above. It is seen that if the steroidal B and C rings are placed on the site vacated by ADP prior to formation of the ouabain-sensitive E 2-P intermediate, then the lactone ring carbonyl position is able to interact with the phosphoenzyme phosphate group and may thus form a mixed anhydride.