Skip to main content

Advertisement

SpringerLink
Log in

Isoflavones as modulators of adenosine monophosphate-activated protein kinase

  • Article
  • Published:
Applied Biological Chemistry Submit manuscript

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is expressed in all eukaryotic cells and can therefore be found in vertebrates, invertebrates, and plants. Since AMPK participates in the regulation of homeostasis on various levels, small compounds that can modulate AMPK activity could be valuable research tools. Several flavonoids can modulate AMPK. Here we investigated the modulatory effect of 37 isoflavones on AMPK activity using an in vitro kinase assay. Because the relationship between the structural properties of flavonoids and their modulatory activities has not been elucidated yet, we used comparative molecular field analysis to derive the structural conditions for modulation of AMPK activity. The molecular binding mode of isoflavones to AMPK was elucidated using in silico docking studies. The findings presented here can aid in the design of new modulators with better specificity for AMPK.

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

Similar content being viewed by others

References

  • Ahn TG, Yang G, Lee HM, Kim MD, Choi HY, Park KS, Lee SD, Kook YB, An HJ (2013) Molecular mechanisms underlying the anti-obesity potential of prunetin, an O-methylated isoflavone. Biochem Pharmacol 85:1525–1533

    Article  CAS  Google Scholar 

  • Andersen C, Kotowska D, Tortzen CG, Kristiansen K, Nielsen J, Petersen RK (2014) 2-(2-Bromophenyl)-formononetin and 2-heptyl-formononetin are PPARgamma partial agonists and reduce lipid accumulation in 3T3-L1 adipocytes. Bioorg Med Chem 22:6105–6111

    Article  CAS  Google Scholar 

  • Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, Issandou M (2006) Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 47:1281–1288

    Article  CAS  Google Scholar 

  • Carling D (2004) The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci 29:18–24

    Article  CAS  Google Scholar 

  • Cheong SH, Furuhashi K, Ito K, Nagaoka M, Yonezawa T, Miura Y, Yagasaki K (2014) Daidzein promotes glucose uptake through glucose transporter 4 translocation to plasma membrane in L6 myocytes and improves glucose homeostasis in Type 2 diabetic model mice. J Nutr Biochem 25:136–143

    Article  CAS  Google Scholar 

  • Choi JS, Ali MY, Jung HA, Oh SH, Choi RJ, Kim EJ (2015) Protein tyrosine phosphatase 1B inhibitory activity of alkaloids from Rhizoma Coptidis and their molecular docking studies. J Ethnopharmacol 171:28–36

    Article  CAS  Google Scholar 

  • Ghillebert R, Swinnen E, Wen J, Vandesteene L, Ramon M, Norga K, Rolland F, Winderickx J (2011) The AMPK/SNF1/SnRK1 fuel gauge and energy regulator: structure, function and regulation. FEBS J 278:3978–3990

    Article  CAS  Google Scholar 

  • Goransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K (2007) Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem 282:32549–32560

    Article  Google Scholar 

  • Hajiaghaalipour F, Khalilpourfarshbafi M, Arya A (2015) Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus. Int J Biol Sci 11:508–524

    Article  CAS  Google Scholar 

  • Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120

    Article  CAS  Google Scholar 

  • Hardie DG, Ross FA, Hawley SA (2012) AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol 19:1222–1236

    Article  CAS  Google Scholar 

  • Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (1996) Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271:27879–27887

    Article  CAS  Google Scholar 

  • Hyun J, Shin SY, So KM, Lee YH, Lim Y (2012) Isoflavones inhibit the clonogenicity of human colon cancer cells. Bioorg Med Chem Lett 22:2664–2669

    Article  CAS  Google Scholar 

  • Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403

    Article  CAS  Google Scholar 

  • Kramer B, Rarey M, Lengauer T (1999) Evaluation of the FLEXX incremental construction algorithm for protein-ligand docking. Proteins 37:228–241

    Article  CAS  Google Scholar 

  • Laderoute KR, Calaoagan JM, Madrid PB, Klon AE, Ehrlich PJ (2010) SU11248 (sunitinib) directly inhibits the activity of mammalian 5’-AMP-activated protein kinase (AMPK). Cancer Biol Ther 10:68–76

    Article  CAS  Google Scholar 

  • Lee Y, Naseem RH, Park BH, Garry DJ, Richardson JA, Schaffer JE, Unger RH (2006) Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem Biophys Res Commun 344:446–452

    Article  CAS  Google Scholar 

  • Li X, Wang L, Zhou XE, Ke J, de Waal PW, Gu X, Tan MH, Wang D, Wu D, Xu HE, Melcher K (2015) Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res 25:50–66

    Article  Google Scholar 

  • Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, Witters LA, Kemp BE (1994) Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem 269:2361–2364

    CAS  Google Scholar 

  • Munday MR, Campbell DG, Carling D, Hardie DG (1988) Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur J Biochem 175:331–338

    Article  CAS  Google Scholar 

  • Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081

    Article  CAS  Google Scholar 

  • Noh BK, Lee JK, Jun HJ, Lee JH, Jia Y, Hoang MH, Kim JW, Park KH, Lee SJ (2011) Restoration of autophagy by puerarin in ethanol-treated hepatocytes via the activation of AMP-activated protein kinase. Biochem Biophys Res Commun 414:361–366

    Article  CAS  Google Scholar 

  • Palacios-Gonzalez B, Zarain-Herzberg A, Flores-Galicia I, Noriega LG, Aleman-Escondrillas G, Zarinan T, Ulloa-Aguirre A, Torres N, Tovar AR (2014) Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle. Biochim Biophys Acta 1841:132–140

    Article  CAS  Google Scholar 

  • Pirhadi S, Ghasemi JB (2010) 3D-QSAR analysis of human immunodeficiency virus entry-1 inhibitors by CoMFA and CoMSIA. Eur J Med Chem 45:4897–4903

    Article  CAS  Google Scholar 

  • Sanchez Y, Amran D, Fernandez C, de Blas E, Aller P (2008) Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK). Int J Cancer 123:1205–1214

    Article  CAS  Google Scholar 

  • Shin SY, Yoon H, Hwang D, Ahn S, Kim DW, Koh D, Lee YH, Lim Y (2013) Benzochalcones bearing pyrazoline moieties show anti-colorectal cancer activities and selective inhibitory effects on aurora kinases. Bioorg Med Chem 21:7018–7024

    Article  CAS  Google Scholar 

  • Shin SY, Jung H, Ahn S, Hwang D, Yoon H, Hyun J, Yong Y, Cho HJ, Koh D, Lee YH, Lim Y (2014) Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells. Bioorg Med Chem 22:1809–1820

    Article  CAS  Google Scholar 

  • Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078

    Article  CAS  Google Scholar 

  • Wang Z, Huo J, Sun L, Wang Y, Jin H, Yu H, Zhang L, Zhou L (2011) Computer-aided drug design for AMP-activated protein kinase activators. Curr Comput Aided Drug Des 7:214–227

    Article  Google Scholar 

  • Wu C, Luan H, Wang S, Zhang X, Wang R, Jin L, Guo P, Chen X (2013) Modulation of lipogenesis and glucose consumption in HepG2 cells and C2C12 myotubes by sophoricoside. Molecules 18:15624–15635

    Article  CAS  Google Scholar 

  • Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ (2013) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:3017–3026

    Google Scholar 

  • Yong Y, Shin SY, Jung Y, Jung H, Ahn S, Chong Y, Lim Y (2015) Flavonoids activating adenosine monophosphate-activated protein kinase. J Korean Soc Appl Biol Chem 58:13–19

    Article  CAS  Google Scholar 

  • Yoon H, Kim TW, Shin SY, Park MJ, Yong Y, Kim DW, Islam T, Lee YH, Jung KY, Lim Y (2013) Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells. Bioorg Med Chem Lett 23:232–238

    Article  CAS  Google Scholar 

  • Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191

    Article  CAS  Google Scholar 

  • Zubieta C, He XZ, Dixon RA, Noel JP (2001) Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases. Nat Struct Biol 8:271–279

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This paper was supported by Konkuk University in 2013.

Author information

Author notes

    Authors and Affiliations

    1. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, 143-701, Korea

      Hyeryoung Jung, Seunghyun Ahn, Beum Soo Kim & Yoongho Lim

    2. Department of Biological Sciences, Konkuk University, Seoul, 143-701, Korea

      Soon Young Shin & Young Han Lee

    Authors
    1. Hyeryoung Jung
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Seunghyun Ahn
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Beum Soo Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Soon Young Shin
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Young Han Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yoongho Lim
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yoongho Lim.

    Additional information

    H. Jung and S. Ahn have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOC 2540 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jung, H., Ahn, S., Kim, B.S. et al. Isoflavones as modulators of adenosine monophosphate-activated protein kinase. Appl Biol Chem 59, 217–225 (2016). https://doi.org/10.1007/s13765-016-0149-8

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13765-016-0149-8

    Keywords

    Search

    Navigation