Mechanism of the Na,K-ATPase Inhibition by MCS Derivatives

Stimac, Robert M.; Kerek, Franz; Apell, Hans-Jürgen

doi:10.1007/s00232-005-0767-2

Cited by 4 publications

(12 citation statements)

References 28 publications

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“…The ion-sensitive nature of our ATPase inhibitory factors MCS (disclosed as SOSA) was remarked in Ref. ( 60 ) assuming that the concentration of the Na + and of other ions may cause significant structural rearrangements. The in vitro ion-sensitive structure of SOSA is also supported by DLS measurements.…”

Section: Sosa As Possible Endogenous Factormentioning

confidence: 84%

“…The mechanism of Na + /K + -ATPase inhibition by the MCS factor was investigated with the fluorescent styryl dye RH421, a dye known to reflect changes of local electric fields in the membrane dielectric. It was found that the binding of the MCS to the Na + /K + -ATPase is not competitive with ouabain ( 59 , 60 ). MCS factors interact with the Na + /K + -ATPase in the E1 conformation of the ion pump and induce a structural rearrangement that causes a change of the equilibrium dissociation constant for one of the first 2 intracellular cation binding sites.…”

Section: Atpase Inhibitory Mcs-factorsmentioning

confidence: 99%

“…MCS factors interact with the Na + /K + -ATPase in the E1 conformation of the ion pump and induce a structural rearrangement that causes a change of the equilibrium dissociation constant for one of the first 2 intracellular cation binding sites. The MCS-inhibited state was found to have bound one cation (H + , Na + , or K + ) in one of two non Na + specific binding sites, and the other Na + ion was bound at high Na + concentrations to the highly Na + -selective ion-binding site ( 60 ).…”

Section: Atpase Inhibitory Mcs-factorsmentioning

confidence: 99%

“…The interaction of SOSA with the ATPase protein is assumed on the cytoplasmic site of the ATPases in the E1 conformation as revealed by charge transfer investigations with the dye RH421 ( 60 ). According to these data, SOSA should inhibit the X1E1 state, manifesting complex interactions with different X ions (Na + , K + , or H + ) and with Na + ions in the (Na)NaE1 state.…”

Section: Sosa As Possible Endogenous Factormentioning

confidence: 99%

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Spherical Oligo-Silicic Acid SOSA Disclosed as Possible Endogenous Digitalis-Like Factor

Kerek¹,

Voicu

2015

Front. Endocrinol.

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The Na+/K+-ATPase is a membrane ion-transporter protein, specifically inhibited by digitalis glycosides used in cardiac therapy. The existence in mammals of some endogenous digitalis-like factors (EDLFs) as presumed ATPase ligands is generally accepted. But the chemical structure of these factors remained elusive because no weighable amounts of pure EDLFs have been isolated. Recent high-resolution crystal structure data of Na+/K+-ATPase have located the hydrophobic binding pocket of the steroid glycoside ouabain. It remained uncertain if the EDLF are targeting this steroid-receptor or another specific binding site(s). Our recently disclosed spherical oligo-silicic acids (SOSA) fulfill the main criteria to be identified with the presumed EDL factors. SOSA was found as a very potent inhibitor of the Na+/K+-ATPase, Ca2+-ATPase, H+/K+-ATPase, and of K-dp-ATPase, with IC50 values between 0.2 and 0.5 μg/mL. These findings are even more astonishing while so far, neither monosilicic acid nor its poly-condensed forms have been remarked biologically active. With the diameter ϕ between 1 and 3 nm, SOSA still belong to molecular species definitely smaller than silica nano-particles with ϕ > 5 nm. In SOSA molecules, almost all Si-OH bonds are displayed on the external shell, which facilitates the binding to hydrophilic ATPase domains. SOSA is stable for long term in solution but is sensitive to freeze-drying, which could explain the failure of countless attempts to isolate pure EDLF. There is a strong resemblance between SOSA and vanadates, the previously known general inhibitors of P-type ATPases. SOSA may be generated endogenously by spherical oligomerization of the ubiquitously present monosilicic acid in animal fluids. The structure of SOSA is sensitive to the concentration of Na+, K+, Ca2+, Mg2+, and other ions suggesting a presumably archaic mechanism for the regulation of the ATPase pumps.

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Section: Sosa As Possible Endogenous Factormentioning

confidence: 84%

Section: Atpase Inhibitory Mcs-factorsmentioning

confidence: 99%

Section: Atpase Inhibitory Mcs-factorsmentioning

confidence: 99%

Section: Sosa As Possible Endogenous Factormentioning

confidence: 99%

See 2 more Smart Citations

Spherical Oligo-Silicic Acid SOSA Disclosed as Possible Endogenous Digitalis-Like Factor

Kerek¹,

Voicu

2015

Front. Endocrinol.

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“…Macrocyclic carbon suboxide (MCS) factors are potent inorganic inhibitors, inhibiting not only Na + K + ‐ATPase but also several P‐type ATPases sharing many properties with putative endogenous digitalis‐like factors. Macrocyclic carbon suboxide factors interact with the cytoplasmic side but not with the extracellular ouabain binding site in contrast to the cardiac‐steroid‐like inhibitors of the Na + K + ‐ATPase (50). Inhibitor 2‐methoxy‐3,8,9‐trihydroxy coumestan (PCALC36) is a non‐steroidal skeleton, which inhibits the Na + K + ‐ATPase by a mechanism of action different from the cardiac glycosides, forming a very stable complex with Na + K + ‐ATPase and serve as a structural paradigm to develop new inotropic drugs.…”

Section: Inhibitors and Their Mechanism Of Actionmentioning

confidence: 99%

The Nucleotide, Inhibitor, and Cation Binding Sites of P‐type II ATPases

Chourasia

Sastry

2012

Chem Biol Drug Des

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P-type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport and expulsion of toxic ions from cells. The harmonized toggling of gates in the extra-and intracellular domains explain the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P-type ATPases requires detailed knowledge of thermodynamical, structural, and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca 2+ -ATPase between E1 and E2 transition states have given a impetus to the theorists to work on the Na + K + -and H + K + -ATPase to address important questions about their function. The current review delineates the importance of cation, nucleotide, and inhibitor binding domains, with a focus on the therapeutic potential and biological relevance of the three P-type II ATPases. This will give an insight into the ion selectivity and their conduction across the transmembrane helices of P-type II ATPases, which may pave the way to a range of fundamental questions about the mechanism and aid in the efforts of structure-and analog-based drug design.

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Palytoxin-induced Effects on Partial Reactions of the Na,K-ATPase

Harmel

Apell

2006

The Journal of General Physiology

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The interaction of palytoxin with the Na,K-ATPase was studied by the electrochromic styryl dye RH421, which monitors the amount of ions in the membrane domain of the pump. The toxin affected the pump function in the state P-E2, independently of the type of phosphorylation (ATP or inorganic phosphate). The palytoxin-induced modification of the protein consisted of two steps: toxin binding and a subsequent conformational change into a transmembrane ion channel. At 20°C, the rate-limiting reaction had a forward rate constant of 105 M−1s−1 and a backward rate constant of about 10−3 s−1. In the palytoxin-modified state, the binding affinity for Na+ and H+ was increased and reached values between those obtained in the E1 and P-E2 conformation under physiological conditions. Even under saturating palytoxin concentrations, the ATPase activity was not completely inhibited. In the Na/K mode, ∼50% of the enzyme remained active in the average, and in the Na-only mode 25%. The experimental findings indicate that an additional exit from the inhibited state exists. An obvious reaction pathway is a slow dephosphorylation of the palytoxin-inhibited state with a time constant of ∼100 s. Analysis of the effect of blockers of the extracellular and cytoplasmic access channels, TPA+ and Br2-Titu3+, respectively, showed that both access channels are part of the ion pathway in the palytoxin-modified protein. All experiments can be explained by an extension of the Post-Albers cycle, in which three additional states were added that branch off in the P-E2 state and lead to states in which the open-channel conformation is introduced and returns into the pump cycle in the occluded E2 state. The previously suggested molecular model for the channel state of the Na,K-ATPase as a conformation in which both gates between binding sites and aqueous phases are simultaneously in their open state is supported by this study.

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Mechanism of the Na,K-ATPase Inhibition by MCS Derivatives

Cited by 4 publications

References 28 publications

Spherical Oligo-Silicic Acid SOSA Disclosed as Possible Endogenous Digitalis-Like Factor

Spherical Oligo-Silicic Acid SOSA Disclosed as Possible Endogenous Digitalis-Like Factor

The Nucleotide, Inhibitor, and Cation Binding Sites of P‐type II ATPases

Palytoxin-induced Effects on Partial Reactions of the Na,K-ATPase

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