Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop

Karl  Weigand; Mette Laursen; Herman G.P. Swarts; Anthonius H.J. Engwerda; Christian  Prufert; Julia  Sandrock; Poul Nissen; Natalya Fedosova; Frank G.M. Russel; Jan B. Koenderink

doi:10.1021/tx500290k

Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop

Karl Weigand, Mette Laursen, Herman G.P. Swarts, Anthonius H.J. Engwerda, Christian Prufert, Julia Sandrock, Poul Nissen, Natalya Fedosova, Frank G.M. Russel, Jan B. Koenderink

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Digitalis-like compounds (DLCs) comprise a diverse group of molecules characterized by a cis-trans-cis ring-fused steroid core linked to a lactone. They have been used in the treatment of different medical problems including heart failure, where their inotropic effect on heart muscle is attributed to potent Na(+),K(+)-ATPase inhibition. Their application as drugs, however, has declined in recent past years due to their small safety margin. Since human Na(+),K(+)-ATPase is represented by four different isoforms expressed in a tissue-specific manner, one of the possibilities to improve the therapeutic index of DLCs is to exploit and amend their isoform selectivity. Here, we aimed to reveal the determinants of selectivity of the ubiquitously expressed α1 isoform and the more restricted α2 isoform toward several well-known DLCs and their hydrogenated forms. Using baculovirus to express various mutants of the α2 isoform, we were able to link residues Met(119) and Ser(124) to differences in affinity between the α1 and α2 isoforms to ouabain, dihydro-ouabain, digoxin, and dihydro-digoxin. We speculate that the interactions between these amino acids and DLCs affect the initial binding of these DLCs. Also, we observed isoform selectivity for DLCs containing no sugar groups.

Original language	English
Journal	Chemical Research in Toxicology
Volume	27
Issue	12
Pages (from-to)	2082-2092
Number of pages	11
ISSN	0893-228X
DOIs	https://doi.org/10.1021/tx500290k
Publication status	Published - 2014

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Weigand, K., Laursen, M., Swarts, H. G. P., Engwerda, A. H. J., Prufert, C., Sandrock, J., Nissen, P., Fedosova, N., Russel, F. G. M., & Koenderink, J. B. (2014). Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop. Chemical Research in Toxicology, 27(12), 2082-2092. https://doi.org/10.1021/tx500290k

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title = "Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop",

abstract = "Digitalis-like compounds (DLCs) comprise a diverse group of molecules characterized by a cis-trans-cis ring-fused steroid core linked to a lactone. They have been used in the treatment of different medical problems including heart failure, where their inotropic effect on heart muscle is attributed to potent Na(+),K(+)-ATPase inhibition. Their application as drugs, however, has declined in recent past years due to their small safety margin. Since human Na(+),K(+)-ATPase is represented by four different isoforms expressed in a tissue-specific manner, one of the possibilities to improve the therapeutic index of DLCs is to exploit and amend their isoform selectivity. Here, we aimed to reveal the determinants of selectivity of the ubiquitously expressed α1 isoform and the more restricted α2 isoform toward several well-known DLCs and their hydrogenated forms. Using baculovirus to express various mutants of the α2 isoform, we were able to link residues Met(119) and Ser(124) to differences in affinity between the α1 and α2 isoforms to ouabain, dihydro-ouabain, digoxin, and dihydro-digoxin. We speculate that the interactions between these amino acids and DLCs affect the initial binding of these DLCs. Also, we observed isoform selectivity for DLCs containing no sugar groups.",

author = "Karl Weigand and Mette Laursen and Swarts, {Herman G.P.} and Engwerda, {Anthonius H.J.} and Christian Prufert and Julia Sandrock and Poul Nissen and Natalya Fedosova and Russel, {Frank G.M.} and Koenderink, {Jan B.}",

year = "2014",

doi = "10.1021/tx500290k",

language = "English",

volume = "27",

pages = "2082--2092",

journal = "Chemical Research in Toxicology",

issn = "0893-228X",

publisher = "American Chemical Society",

number = "12",

}

Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop. / Weigand, Karl ; Laursen, Mette; Swarts, Herman G.P. et al.
In: Chemical Research in Toxicology, Vol. 27, No. 12, 2014, p. 2082-2092.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop

AU - Weigand, Karl

AU - Laursen, Mette

AU - Swarts, Herman G.P.

AU - Engwerda, Anthonius H.J.

AU - Prufert, Christian

AU - Sandrock, Julia

AU - Nissen, Poul

AU - Fedosova, Natalya

AU - Russel, Frank G.M.

AU - Koenderink, Jan B.

PY - 2014

Y1 - 2014

N2 - Digitalis-like compounds (DLCs) comprise a diverse group of molecules characterized by a cis-trans-cis ring-fused steroid core linked to a lactone. They have been used in the treatment of different medical problems including heart failure, where their inotropic effect on heart muscle is attributed to potent Na(+),K(+)-ATPase inhibition. Their application as drugs, however, has declined in recent past years due to their small safety margin. Since human Na(+),K(+)-ATPase is represented by four different isoforms expressed in a tissue-specific manner, one of the possibilities to improve the therapeutic index of DLCs is to exploit and amend their isoform selectivity. Here, we aimed to reveal the determinants of selectivity of the ubiquitously expressed α1 isoform and the more restricted α2 isoform toward several well-known DLCs and their hydrogenated forms. Using baculovirus to express various mutants of the α2 isoform, we were able to link residues Met(119) and Ser(124) to differences in affinity between the α1 and α2 isoforms to ouabain, dihydro-ouabain, digoxin, and dihydro-digoxin. We speculate that the interactions between these amino acids and DLCs affect the initial binding of these DLCs. Also, we observed isoform selectivity for DLCs containing no sugar groups.

AB - Digitalis-like compounds (DLCs) comprise a diverse group of molecules characterized by a cis-trans-cis ring-fused steroid core linked to a lactone. They have been used in the treatment of different medical problems including heart failure, where their inotropic effect on heart muscle is attributed to potent Na(+),K(+)-ATPase inhibition. Their application as drugs, however, has declined in recent past years due to their small safety margin. Since human Na(+),K(+)-ATPase is represented by four different isoforms expressed in a tissue-specific manner, one of the possibilities to improve the therapeutic index of DLCs is to exploit and amend their isoform selectivity. Here, we aimed to reveal the determinants of selectivity of the ubiquitously expressed α1 isoform and the more restricted α2 isoform toward several well-known DLCs and their hydrogenated forms. Using baculovirus to express various mutants of the α2 isoform, we were able to link residues Met(119) and Ser(124) to differences in affinity between the α1 and α2 isoforms to ouabain, dihydro-ouabain, digoxin, and dihydro-digoxin. We speculate that the interactions between these amino acids and DLCs affect the initial binding of these DLCs. Also, we observed isoform selectivity for DLCs containing no sugar groups.

U2 - 10.1021/tx500290k

DO - 10.1021/tx500290k

M3 - Journal article

C2 - 25361285

SN - 0893-228X

VL - 27

SP - 2082

EP - 2092

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

IS - 12

ER -

Na(+),K(+)-ATPase Isoform Selectivity for Digitalis-Like Compounds Is Determined by Two Amino Acids in the First Extracellular Loop

Abstract

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