Skip to main content
SpringerLink
Log in

Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives

  • Original Paper
  • Published:
Journal of Muscle Research and Cell Motility Aims and scope Submit manuscript

Abstract

The effect of lipophilic rutin derivatives (acylated with fatty acid chain length of 16–22) on sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1 isoform) compared to the parent molecule rutin was evaluated. Rutin derivatives caused concentration dependent decrease of SERCA1 activity (IC50 ~ 23–64 µM) and significant conformational alterations in the transmembrane region of the enzyme. Upon treatment by peroxynitrite, rutin derivatives exerted a hormetic effect, i.e. prevented enzyme activity decrease at low concentrations, while additionally inhibited at high concentrations. Concerning the posttranslational modifications of SERCA1, rutin esters: (i) induced a significant loss of free sulfhydryl groups, (ii) protected the enzyme from protein carbonyl formation, and (iii) prevented SERCA from tyrosine nitration (except R20:4 and R22:1). In silico study revealed a strong affinity of the derivative R20:4 to the transmembrane region of SERCA1, stabilized via hydrogen bonds with Glu90, Glu771, Thr778 and Thr848 residues. Interaction of rutin derivatives with Glu771, a residue involved in Ca2+ binding, is likely to be responsible for the inhibitory effect of the esters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

SR Ca2+-ATPase:

Sarcoplasmic reticulum calcium-dependent adenosine triphosphatase

FITC:

Fluorescein-5-isothiocyanate

IC50 :

Half-maximal inhibitory concentration

NCD-4:

N-cyclohexyl-N′-(4-dimethylamino-l-naphthyl) carbodiimide

3-NT:

3-Nitrotyrosine

ONOO− :

Peroxynitrite anion

PCOs:

Protein carbonyls

R:

Rutin

R16:

Rutin palmitate

R18:1:

Rutin oleate

R18:2:

Rutin linoleate

R18:3:

Rutin linolenate

R20:4:

Rutin arachidonate

R22:1:

Rutin erucate

SERCA1:

Skeletal muscle sarco/endoplasmic reticulum Ca2+–ATPase, isoform 1

TG1:

Methyl-10-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-9-methoxy-3-oxo-3Hbenzo-[f]chromene-2-carboxylate

References

  • Alvarez MN, Piacenza L, Irigoín F et al (2004) Macrophage-derived peroxynitrite diffusion and toxicity to Trypanosoma cruzi. Arch Biochem Biophys 432:222–232

    Article  CAS  PubMed  Google Scholar 

  • Bilmen JG, Khan SZ, Javed MH, Michelangeli F (2001) Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP. Eur J Biochem 268:6318–6327

    Article  CAS  PubMed  Google Scholar 

  • Bloor SJ, Abrahams S (2002) The structure of the major anthocyanin in Arabidopsis thaliana. Phytochemistry 59:343–346

    Article  CAS  PubMed  Google Scholar 

  • Buss H, Chan TP, Sluis KB et al (1997) Protein carbonyl measurement by a sensitive ELISA method. Free Radic Biol Med 23:361–366

    Article  CAS  PubMed  Google Scholar 

  • Carney J, East JM, Lee AG (2007) Penetration of lipid chains into transmembrane surfaces of membrane proteins: studies with MscL. Biophys J 92:3556–3563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chou C-C, Yang J-S, Lu H-F et al (2010) Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res 33:1181–1191

    Article  CAS  PubMed  Google Scholar 

  • Cohen RA, Adachi T (2006) Nitric-oxide-induced vasodilatation: regulation by physiologic s-glutathiolation and pathologic oxidation of the sarcoplasmic endoplasmic reticulum calcium ATPase. Trends Cardiovasc Med 16:109–114

    Article  CAS  PubMed  Google Scholar 

  • Ferrer J-L, Austin MB, Stewart C, Noel JP (2008) Structure and function of enzymes involved in the biosynthesis of phenylpropanoids. Plant Physiol Biochem 46:356–370

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Froud RJ, Lee AG (1986) Conformational transitions in the Ca2+ + Mg2+-activated ATPase and the binding of Ca2+ ions. Biochem J 237:197–206

    PubMed Central  CAS  PubMed  Google Scholar 

  • Froud RJ, Earl CR, East JM, Lee AG (1986) Effects of lipid fatty acyl chain structure on the activity of the (Ca2+ + Mg2+)-ATPase. Biochim Biophys Acta 860:354–360

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara H, Tanaka Y, Yonekura-Sakakibara K et al (1998) cDNA cloning, gene expression and subcellular localization of anthocyanin 5-aromatic acyltransferase from Gentiana triflora. Plant J 16:421–431

    Article  CAS  PubMed  Google Scholar 

  • Grover AK, Kwan C-Y, Samson SE (2003) Effects of peroxynitrite on sarco/endoplasmic reticulum Ca2+ pump isoforms SERCA2b and SERCA3a. Am J Physiol Cell Physiol 285:C1537–C1543

    Article  CAS  PubMed  Google Scholar 

  • Gutiérrez-Martín Y, Martín-Romero FJ, Iñesta-Vaquera FA et al (2004) Modulation of sarcoplasmic reticulum Ca(2+)-ATPase by chronic and acute exposure to peroxynitrite. Eur J Biochem 271:2647–2657

    Article  PubMed  Google Scholar 

  • Hidalgo C, Thomas DD, Ikemoto N (1978) Effect of lipid environment on protein motion and enzymatic activity of the sarcoplasmic reticulum calcium ATPase. J Biol Chem 253:6879–6887

    CAS  PubMed  Google Scholar 

  • International Agency for Research on Cancer (1999) Quercetin. Some chemicals that cause tumours of the kidney or urinary bladder in rodents and some other substances. IARC Monogr Eval Carcinog. Risks to humans, vol. 73. IARC Press, Lyon, France, pp. 497–515

  • Ischiropoulos H, Zhu L, Beckman JS (1992) Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys 298:446–451

    Article  CAS  PubMed  Google Scholar 

  • Karlovská J, Uhríková D, Kucerka N et al (2006) Influence of N-dodecyl-N,N-dimethylamine N-oxide on the activity of sarcoplasmic reticulum Ca(2+)-transporting ATPase reconstituted into diacylphosphatidylcholine vesicles: efects of bilayer physical parameters. Biophys Chem 119:69–77

    Article  PubMed  Google Scholar 

  • Kim DW, Hwang IK, Lim SS et al (2009) Germinated Buckwheat extract decreases blood pressure and nitrotyrosine immunoreactivity in aortic endothelial cells in spontaneously hypertensive rats. Phytother Res 23:993–998

    Article  CAS  PubMed  Google Scholar 

  • Klebl BM, Ayoub AT, Pette D (1998) Protein oxidation, tyrosine nitration, and inactivation of sarcoplasmic reticulum Ca2+-ATPase in low-frequency stimulated rabbit muscle. FEBS Lett 422:381–384

    Article  CAS  PubMed  Google Scholar 

  • Kodelia G, Athanasiou K, Kolisis FN (1994) Enzymatic synthesis of butyryl-rutin ester in organic solvents and its cytogenetic effects in mammalian cells in culture. Appl Biochem Biotechnol 44:205–212

    Article  CAS  PubMed  Google Scholar 

  • Krieger E, Koraimann G, Vriend G (2002) Increasing the precision of comparative models with YASARA NOVA: a self-parameterizing force field. Proteins 47:393–402

    Article  CAS  PubMed  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  • Lancel S, Qin F, Lennon SL et al (2010) Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice. Circ Res 107:228–232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee AG (2002) Ca2+-ATPase structure in the E1 and E2 conformations: mechanism, helix–helix and helix–lipid interactions. Biochim Biophys Acta 1565:246–266

    Article  CAS  PubMed  Google Scholar 

  • Lenoir G, Menguy T, Corre F et al (2002) Overproduction in yeast and rapid and efficient purification of the rabbit SERCA1a Ca(2+)-ATPase. Biochim Biophys Acta 1560:67–83

    Article  CAS  PubMed  Google Scholar 

  • Lin SF, Lin Y-H, Lin M et al (2010) Synthesis and structure-activity relationship of 3-O-acylated (-)-epigallocatechins as 5α-reductase inhibitors. Eur J Med Chem 45:6068–6076

    Article  CAS  PubMed  Google Scholar 

  • Mahmoud I (2001) Acylated flavonol glycosides from Eugenia jambolana leaves. Phytochemistry 58:1239–1244

    Article  CAS  PubMed  Google Scholar 

  • Michelangeli F, East JM (2011) A diversity of SERCA Ca2+ pump inhibitors. Biochem Soc Trans 39:789–797

    CAS  PubMed  Google Scholar 

  • Munkonge F, East JM, Lee AG (1989) Positions of the sites labeled by N-cyclohexyl-N′-(4-dimethylamino-1-naphthyl)carbodiimide on the (Ca2+ + Mg2+)-ATPase. Biochim Biophys Acta 979:113–120

    Article  CAS  PubMed  Google Scholar 

  • National Toxicology Program (1992) Toxicology and carcinogenesis studies of quercetin (CAS No. 117-39-5) in F344 Rats (Feed Studies). Natl Toxicol Program Tech Rep Ser 409:1–171

    Google Scholar 

  • Ogunbayo OA, Michelangeli F (2014) Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca(2+) ATPase by multimode mechanisms. FEBS J 281:766–777

    Article  CAS  PubMed  Google Scholar 

  • Ogunbayo OA, Harris RM, Waring RH et al (2008) Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by flavonoids: a quantitative structure-activity relationship study. IUBMB Life 60:853–858

    Article  CAS  PubMed  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266:4244–4250

    CAS  PubMed  Google Scholar 

  • Restall CJ, Coke M, Phillips E, Chapman D (1986) Derivative spectroscopy of tryptophan fluorescence used to study conformational transitions in the (Ca2+ + Mg2+)-adenosine triphosphatase of sarcoplasmic reticulum. Biochim Biophys Acta 874:305–311

    Article  CAS  PubMed  Google Scholar 

  • Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956

    Article  CAS  PubMed  Google Scholar 

  • Sagara Y, Inesi G (1991) Inhibition of the sarcoplasmic reticulum Ca2+ transport ATPase by thapsigargin at subnanomolar concentrations. J Biol Chem 266:13503–13506

    CAS  PubMed  Google Scholar 

  • Salem JH, Chevalot I, Harscoat-Schiavo C et al (2011) Biological activities of flavonoids from Nitraria retusa (Forssk.) Asch. and their acylated derivatives. Food Chem 124:486–494

    Article  Google Scholar 

  • Schöneich C, Viner RI, Ferrington DA, Bigelow DJ (1999) Age-related chemical modification of the skeletal muscle sarcoplasmic reticulum Ca-ATPase of the rat. Mech Ageing Dev 107:221–231

    Article  PubMed  Google Scholar 

  • Shao Y, Molnar LF, Jung Y et al (2006) Advances in methods and algorithms in a modern quantum chemistry program package. Phys Chem Chem Phys 8:3172–3191

    Article  CAS  PubMed  Google Scholar 

  • Sharov VS, Dremina ES, Galeva NA et al (2006) Quantitative mapping of oxidation-sensitive cysteine residues in SERCA in vivo and in vitro by HPLC-electrospray-tandem MS: selective protein oxidation during biological aging. Biochem J 394:605–615

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spencer JPE (2007) The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2:257–273

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spencer JPE, Rice-Evans C, Williams RJ (2003) Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278:34783–34793

    Article  CAS  PubMed  Google Scholar 

  • Strosova M, Karlovska J, Spickett CM et al (2009) Oxidative injury induced by hypochlorous acid to Ca-ATPase from sarcoplasmic reticulum of skeletal muscle and protective effect of trolox. Gen Physiol Biophys 28:195–209

    Article  CAS  PubMed  Google Scholar 

  • Strosova MK, Karlovska J, Zizkova P et al (2011) Modulation of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase activity and oxidative modification during the development of adjuvant arthritis. Arch Biochem Biophys 511:40–47

    Article  CAS  PubMed  Google Scholar 

  • Suda I, Oki T, Masuda M et al (2002) Direct absorption of acylated anthocyanin in purple-fleshed sweet potato into rats. J Agric Food Chem 50:1672–1676

    Article  CAS  PubMed  Google Scholar 

  • Sumbilla C, Cantilina T, Collins JH et al (1991) Structural perturbation of the transmembrane region interferes with calcium binding by the Ca2+ transport ATPase. J Biol Chem 266:12682–12689

    CAS  PubMed  Google Scholar 

  • Szabo C, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev 6:662–680

    CAS  Google Scholar 

  • Toyoshima C (2008) Structural aspects of ion pumping by Ca2+-ATPase of sarcoplasmic reticulum. Arch Biochem Biophys 476:3–11

    Article  CAS  PubMed  Google Scholar 

  • Toyoshima C, Nakasako M, Nomura H, Ogawa H (2000) Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature 405:647–655

    Article  CAS  PubMed  Google Scholar 

  • Toyoshima C, Iwasawa S, Ogawa H et al (2013) Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state. Nature 495:260–264

    Article  CAS  PubMed  Google Scholar 

  • Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  CAS  PubMed  Google Scholar 

  • Velasco-Guillén I, Corbalán-García S, Gómez-Fernández JC, Teruel JA (1998) Location of N-cyclohexyl-N′-(4-dimethyl-amino-alpha-naphthyl)carbodiimide-binding site in sarcoplasmic reticulum Ca2+-transporting ATPase. Eur J Biochem 253:339–344

    Article  PubMed  Google Scholar 

  • Viner RI, Hühmer AF, Bigelow DJ, Schöneich C (1996) The oxidative inactivation of sarcoplasmic reticulum Ca(2+)-ATPase by peroxynitrite. Free Radic Res 24:243–259

    Article  CAS  PubMed  Google Scholar 

  • Viner RI, Ferrington DA, Williams TD et al (1999a) Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle. Biochem J 340(Pt 3):657–669

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Viner RI, Williams TD, Schöneich C (1999b) Peroxynitrite modification of protein thiols: oxidation, nitrosylation, and S-glutathiolation of functionally important cysteine residue(s) in the sarcoplasmic reticulum Ca-ATPase. Biochemistry 38:12408–12415

    Article  CAS  PubMed  Google Scholar 

  • Viskupicova J (2009a) Enzymatic lipophilization of glycosylated flavonoids and related compounds with purpose of improvement of their health-promoting properties. Ph.D. Thesis. Slovak University of Technology, Slovakia

  • Viskupicova J, Ondrejovic M, Sturdík E (2009b) The potential and practical applications of acylated flavonoids. Pharmazie 64:355–360

    CAS  PubMed  Google Scholar 

  • Viskupicova J, Strosova M, Sturdik E, Horakova L (2009c) Modulating effect of flavonoids and their derivatives on sarcoplasmic reticulum Ca2+-ATPase oxidized by hypochloric acid and peroxynitrite. Neuro Endocrinol Lett 30(Suppl 1):148–151

    CAS  PubMed  Google Scholar 

  • Viskupicova J, Danihelova M, Ondrejovic M et al (2010) Lipophilic rutin derivatives for antioxidant protection of oil-based foods. Food Chem 123:45–50

    Article  CAS  Google Scholar 

  • Wagner S, Rokita AG, Anderson ME, Maier LS (2013) Redox regulation of sodium and calcium handling. Antioxid Redox Signal 18:1063–1077

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Warren GB, Toon PA, Birdsall NJ et al (1974a) Reconstitution of a calcium pump using defined membrane components. Proc Natl Acad Sci USA 71:622–626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Warren GB, Toon PA, Birdsall NJ et al (1974b) Reversible lipid titrations of the activity of pure adenosine triphosphatase-lipid complexes. Biochemistry 13:5501–5507

    Article  CAS  PubMed  Google Scholar 

  • Wootton LL, Michelangeli F (2006) The effects of the phenylalanine 256 to valine mutation on the sensitivity of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) Ca2+ pump isoforms 1, 2, and 3 to thapsigargin and other inhibitors. J Biol Chem 281:6970–6976

    Article  CAS  PubMed  Google Scholar 

  • Xu S, Ying J, Jiang B et al (2006) Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol 290:H2220–H2227

    Article  CAS  PubMed  Google Scholar 

  • Ying J, Sharov V, Xu S et al (2008) Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca(2+) ATPase in diabetic pig aorta. Free Radic Biol Med 45:756–762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Žižková P, Viskupičová J, Blaškovič D et al (2013) Sarcoplasmic reticulum Ca(2+)-ATPase from rabbit skeletal muscle modified by peroxynitrite. J Enzyme Inhib Med Chem 6:3

    Google Scholar 

Download references

Acknowledgments

This work was supported by the Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF in the frame of the Project “Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases” (ITMS 26240220040), COST Actions CM1001, CM1103, BM1204 and by VEGA Grants 2/0038/11 and 2/0033/14.

Author information

Authors and Affiliations

  1. Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04, Bratislava, Slovakia

    Jana Viskupicova, Magdalena Majekova & Lubica Horakova

Authors
  1. Jana Viskupicova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdalena Majekova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lubica Horakova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jana Viskupicova.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Viskupicova, J., Majekova, M. & Horakova, L. Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives. J Muscle Res Cell Motil 36, 183–194 (2015). https://doi.org/10.1007/s10974-014-9402-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10974-014-9402-0

Keywords

Search

Navigation