RT Journal Article
SR Electronic
T1 Structure-Activity Relationships of Cardiotonic Steroids for the Inhibition of Sodium- and Potassium-Dependent Adenosine Triphosphatase
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 494
OP 500
VO 10
IS 3
A1 ATSUNOBU YODA
A1 SHIZUKO YODA
YR 1974
UL http://molpharm.aspetjournals.org/content/10/3/494.abstract
AB The dissociation rate constants (kd) of cardiac monoglycoside—(Na+ + K+)-ATPase complexes formed in the Na+-Mg2+-ATP system (type I complex) were determined by enzymatic assay after dilution. The kd value of each cardiac glycoside—enzyme complex thus formed was greater than that of the complex formed in the Mg2+-Pi system (type II complex). Whereas the kd values of type II complexes were dependent only on the sugar moiety, the kd values of type I complexes were affected by both the steroid and sugar moieties. For cardiac glycoside—enzyme complexes in which the sugar moiety was the same, the stability of type I complexes increased in the order: digitoxigenin glycoside < strophanthidin glycoside < digoxigenin glycoside and strophanthidin glycoside < ouabagenin glycoside. If the steroid moiety was the same, the stability increased in the order: digitoxide [unknown] 6-deoxyglucoside [unknown] fucoside < 6-deoxyguloside < rhamnoside. Methylation of the sugar 3'-hydroxyl group decreased stability. These data indicate that in type I complexes a sugarspecific site(s) on the enzyme binds the sugar moiety at the 2'-α- and 3'-α or β-hydroxyl groups by hydrogen bond(s), and at the 5'-α-methyl group by a hydrophobic bond. The activation energy of this dissociation was approximately 30 kcal/mol with all the cardiac monoglycosides tested. The differences in kd values between type I and type II complexes indicate that the two are distinct, possibly as a result of conformational differences in the sugar-specific site of the (Na+ + K+)-ATPase. ACKNOWLEDGMENT We thank Dr. Lowell E. Hokin for his interest and thoughtful help with the manuscript.