The thermodynamic essence of the reversible inactivation of Na+/K+-transporting ATPase by various digitalis derivatives is relaxation of enzyme conformational energy.
This paper reports on the kinetic and thermodynamic parameters describing the interaction of selected digitalis derivatives with hog and guinea-pig cardiac (Na+ + K+)-ATPase (Na+/K+-transporting ATPase EC 3.6.1.37). 32 digitalis derivatives were characterized as to the values of the delta G0', delta G----not equal to, and delta G----not equal to quantities in their interaction with (Na+ + K+)-ATPase from hog cardiac muscle in the presence of ATP, Mg2+, Na+ and K+. Nine derivatives were additionally characterized as to the values of the delta H0', delta S0', delta H----not equal to, delta S----not equal to, delta H not equal to, and delta S not equal to quantities in their interaction with the hog enzyme promoted by ATP, Mg2+ and Na+ in the presence or absence of K+. The formation of the inhibitory complexes is in any case an endothermic, entropically driven process. The Gibbs energy barriers in the formation and dissociation of the complexes, delta G----not equal to and delta G----not equal to, are imposed by large, unfavourable delta H not equal to values. K+ decreases the delta G0' value by increasing the delta G----not equal to value more than the delta G----not equal to value. In comparison with hog (Na+ + K+)-ATPase, the interaction of three derivatives with guinea-pig cardiac enzyme in the presence of ATP, Mg2+, Na+ and K+ is characterized by lower delta G0' values caused by lower favourable delta S0' values, and is accompanied by lower delta G----not equal to values. The magnitude of the kinetic parameters and the characteristic of the thermodynamic quantities describing the interaction between various digitalis derivatives and (Na+ + K+)-ATPase, indicate the induction of substantial conformational changes in the enzyme protein. A large entropy gain in the enzyme protein, observed irrespective of enzyme origin and ligation, appears to be the common denominator of the inhibitory action of all digitalis derivatives studied, suggesting that the digitalis-elicited relaxation of high conformational energy (negentropy strain) of the enzyme protein is the thermodynamic essence of the reversible inactivation of (Na+ + K+)-ATPase.
Beer
J
J
Central Institute of Molecular Biology, Academy of Sciences of the GDR, Berlin.
Kunze
R
R
Herrmann
I
I
Portius
H J
HJ
Mirsalichova
N M
NM
Abubakirov
N K
NK
Repke
K R
KR
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004071:Digitalis Glycosides / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology; D011188:Potassium / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine; D013816:Thermodynamics
D004071:Digitalis Glycosides; D000255:Adenosine Triphosphate; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D011188:Potassium