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Biochim Biophys Acta. 1990 May 9;1024(1):32-40.

Binding of unsaturated fatty acids to Na+, K(+)-ATPase leading to inhibition and inactivation.

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Department of Biochemistry, University of Nijmegen, The Netherlands.


The effects of free fatty acids on the mechanism of action of Na+, K(+)-ATPase were studied. Unsaturated free fatty acids (palmitoleic acid, oleic acid, linoleic acid and arachidonic acid) inhibited the Na+, K(+)-ATPase activity within a narrow range, while saturated and methylated fatty acids had little or no effect. The following effects of oleic acid were found: (1) The affinity for K+ on the overall ATPase and the p-nitrophenylphosphatase reaction as well as the maximal activities were decreased. (2) The Na(+)-ATPase activity was also inhibited but the '0'-ATPase activity was hardly changed. (3) The steady-state ATP phosphorylation level in the presence of Na+ was not influenced. (4) The dephosphorylation rate constant of the phosphointermediate was slightly decreased, resulting in elevated phosphorylation levels in the absence of Na+. (5) The inhibitory effect of ATP on the dephosphorylation rate was not affected. (6) The K+ sensitivity of the phosphoenzyme in the presence as well as in the absence of Na+ was decreased. (7) Ouabain binding was inhibited. Both the affinity and the number of binding sites were lowered. In addition it was found that Na+, K(+)-ATPase binds oleic acid linearly with the fatty acid concentration up to more than 100 mol oleic acid per mol alpha beta oligomer of Na+, K(+)-ATPase. Prolonged incubation with oleic acid led to irreversible inactivation of the enzyme. This inactivation was dependent on the reaction conditions: ligands, temperature, enzyme concentration, time and fatty acid concentration. The combined presence of inactivation (long term effects) and the effects on the (K(+)-activated) dephosphorylation (short term effects) explain the mixed type inhibition of free fatty acids as observed in assays for K(+)-activated ATPase, K(+)-activated p-nitrophenylphosphatase and ouabain binding. It also explains the sharp inhibition curve in the Na+, K(+)-ATPase activity test.

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