The P-type ATPase inhibiting potential of polyoxotungstates

Abstract

Polyoxometalates (POMs) are transition metal complexes that exhibit a broad diversity of structures and properties rendering them promising for biological purposes. POMs are able to inhibit a series of biologically important enzymes, including phosphatases, and thus are able to affect many biochemical processes. In the present study, we analyzed and compared the inhibitory effects of nine different polyoxotungstates (POTs) on two P-type ATPases, Ca²⁺-ATPase from skeletal muscle and Na⁺/K⁺-ATPase from basal membrane of skin epithelia. For Ca²⁺-ATPase inhibition, an in vitro study was performed and the strongest inhibitors were determined to be the large heteropolytungstate K₉(C₂H₈N)₅[H₁₀Se₂W₂₉O₁₀₃] (Se₂W₂₉) and the Dawson-type POT K₆[α-P₂W₁₈O₆₂] (P₂W₁₈) exhibiting IC₅₀ values of 0.3 and 0.6 μM, respectively. Promising results were also shown for the Keggin-based POTs K₆H₂[CoW₁₁TiO₄₀] (CoW₁₁Ti, IC₅₀ = 4 μM) and Na₁₀[α-SiW₉O₃₄] (SiW₉, IC₅₀ = 16 μM), K₁₄[As₂W₁₉O₆₇(H₂O)] (As₂W₁₉, IC₅₀ = 28 μM) and the lacunary Dawson K₁₂[α-H₂P₂W₁₂O₄₈] (P₂W₁₂, IC₅₀ = 11 μM), whereas low inhibitory potencies were observed for the isopolytungstate Na₁₂[H₄W₂₂O₇₄] (W₂₂, IC₅₀ = 68 μM) and the Anderson-type Na₆[TeW₆O₂₄] (TeW₆, IC₅₀ = 200 μM). Regarding the inhibition of Na⁺/K⁺-ATPase activity, for the first time an ex vivo study was conducted using the opercular epithelium of killifish in order to investigate the effects of POTs on the epithelial chloride secretion. Interestingly, 1 μM of the most potent Ca²⁺-ATPase inhibitor, Se₂W₂₉, showed only a minor inhibitory effect (14% inhibition) on Na⁺/K⁺-ATPase activity, whereas almost total inhibition (99% inhibition) was achieved using P₂W₁₈. The remaining POTs exhibited similar inhibition rates on both ATPases. These results reveal the high potential of some POTs to act as P-type ATPase inhibitors, with Se₂W₂₉ showing high selectivity towards Ca²⁺-ATPase.