Journal of Chemical Biology

, Volume 4, Issue 3, pp 109–116 | Cite as

Hill coefficients of dietary polyphenolic enzyme inhibitiors: can beneficial health effects of dietary polyphenols be explained by allosteric enzyme denaturing?

  • Nikolai KuhnertEmail author
  • Farnoosh Dairpoosh
  • Rakesh Jaiswal
  • Marius Matei
  • Sagar Deshpande
  • Agnieszka Golon
  • Hany Nour
  • Hande Karaköse
  • Nadim Hourani
Original Article


Inspired by a recent article by Prinz, suggesting that Hill coefficients, obtained from four parameter logistic fits to dose–response curves, represent a parameter allowing distinction between a general allosteric denaturing process and real single site enzyme inhibition, Hill coefficients of a number of selected dietary polyphenol enzyme inhibitions were compiled from the available literature. From available literature data, it is apparent that the majority of polyphenol enzyme interactions reported lead to enzyme inhibition via allosteric denaturing rather than single site inhibition as judged by their reported Hill coefficients. The results of these searches are presented and their implications discussed leading to the suggestion of a novel hypothesis for polyphenol biological activity termed the insect swarm hypothesis.


Polyphenols Enzyme inhibition Human diet 


  1. 1.
    Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D (1993) dietary antioxidant flavonoids and risk of coronary heart-disease - the zutphen elderly study. Lancet 342:1007–1011CrossRefGoogle Scholar
  2. 2.
    Crozier A, Jaganath IB, Clifford MN (2009) Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 26:1001–1043CrossRefGoogle Scholar
  3. 3.
    Williamson G, Manach C (2005) Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr 81:243S–255SGoogle Scholar
  4. 4.
    Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130:2073S–2085SGoogle Scholar
  5. 5.
    RiceEvans CA, Miller J, Paganga G (1997) Antioxidant properties of phenolic compounds. Trends Plant Sci 2:152–159CrossRefGoogle Scholar
  6. 6.
    Halliwell B, Gutteridge JMC, Cross CE (1992) Free-radicals, antioxidants, and human-disease: where are we now? J Lab Clin Med 119:598–620Google Scholar
  7. 7.
    Middleton E, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol Rev 52:673–751Google Scholar
  8. 8.
    Baeuerle PA, Henkel T (1994) Function amd activation of NF-kappa-B in the immune-system. Annu Rev Immunol 12:141–179CrossRefGoogle Scholar
  9. 9.
    Prinz H, Schönichen A (2008) Transient binding patches: a plausible concept for drug binding. J Chem Biol 1:95–104CrossRefGoogle Scholar
  10. 10.
    Prinz H (2010) Hill coefficients, dose response curves and allosteric machanisms. J Chem Biol 2:37–44CrossRefGoogle Scholar
  11. 11.
    Kuhnert N, Le-Gresley A (2005) Synthesis and capsule formation of upper rim substituted tetra-acrylamido calix 4 arenes. Org Biomol Chem 3:2175–2182CrossRefGoogle Scholar
  12. 12.
    Haslam E (1974) Polyphenol-protein interactions. Biochem J 139:285–288Google Scholar
  13. 13.
    McManus JP, Davis KG, Lilley TH, Haslam E (1981) The association of proteins with polyphenols. J Chem Soc Chem Comm 7:309–311CrossRefGoogle Scholar
  14. 14.
    Haslam E (1988) Plant polyphenols (syn vegetable tannins) and chemical defense - a reappraisal. J Chem Ecol 14:1789–1805CrossRefGoogle Scholar
  15. 15.
    Hagerman AE, Butler LG (1978) Protein precipitation method for quantitative-determination of tannins. J Agr Food Chem 26:809–812CrossRefGoogle Scholar
  16. 16.
    Hagerman AE, Butler LG (1980) Determination of protein in tannin-protein precipitates. J Agr Food Chem 28:944–947CrossRefGoogle Scholar
  17. 17.
    Haslam E, Lilley TH (1988) Natural astringency in foodstuffs - a molecular interpretation. Crc Crit Rev Food Sci 27:1–40CrossRefGoogle Scholar
  18. 18.
    Baxter NJ, Lilley TH, Haslam E, Williamson MP (1997) Multiple interactions between polyphenols and a salivary proline-rich protein repeat result in complexation and precipitation. Biochemistry 36:5566–5577CrossRefGoogle Scholar
  19. 19.
    Boze H, Marlin T, Durand D, Perez J, Vernhet A, Canon F, Sarni-Manchado P, Cheynier V, Cabane B (2010) Proline-Rich Salivary Proteins Have Extended Conformations. Biophys J 99:656–665CrossRefGoogle Scholar
  20. 20.
    Canon F, Pate F, Meudec E, Marlin T, Cheynier V, Giuliani A, Sarni-Manchado P (2009) Characterization, stoichiometry, and stability of salivary protein-tannin complexes by ESI-MS and ESI-MS/MS. Anal Bioanal Chem 395:2535–2545CrossRefGoogle Scholar
  21. 21.
    Charlton AJ, Baxter NJ, Khan ML, Moir AJG, Haslam E, Davies AP, Williamson MP (2002) Polyphenol/peptide binding and precipitation. J Agr Food Chem 50:1593–1601CrossRefGoogle Scholar
  22. 22.
    Hagerman AE, Rice ME, Ritchard NT (1998) Mechanisms of protein precipitation for two tannins, pentagalloyl glucose and epicatechin(16) (4 - > 8) catechin (procyanidin). J Agr Food Chem 46:2590–2595CrossRefGoogle Scholar
  23. 23.
    NIH database at (search PubChem bioassay).
  24. 24.
    Liou YM, Kuo SC, Hsieh SR (2008) Differential effects of a green tea-derived polyphenol (-)-epigallocatechin-3-gallate on the acidosis-induced decrease in the Ca2+ sensitivity of cardiac and skeletal muscle. Pflug Arch Eur J Phy 456:787–800CrossRefGoogle Scholar
  25. 25.
    Li M, Allen A, Smith TJ (2007) High throughput screening reveals several new classes of glutamate dehydrogenase inhibitors. Biochemistry 46:15089–15102CrossRefGoogle Scholar
  26. 26.
    Baek WK, Jang BC, Lim JH, Kwon TK, Lee HY, Cho CH, Kim DK, Shin DH, Park JG, Lim JG, Bae JH, Yoo SK, Park WK, Song DK (2005) Inhibitory modulation of ATP-sensitive potassium channels by gallate-ester moiety of (-)-epigallocatechin-3-gallate. Biochem Pharmacol 70:1560–1567CrossRefGoogle Scholar
  27. 27.
    Choi BH, Choi JS, Min DS, Yoon SH, Rhie DJ, Jo YH, Kim MS, Hahn SJ (2001) Effects of (-)-epigallocatechin-3-gallate, the main component of green tea, on the cloned rat brain Kv1.5 potassium channels. Biochem Pharmacol 62:527–535CrossRefGoogle Scholar
  28. 28.
    Lee WJ, Zhu BT (2006) Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis 27:269–277CrossRefGoogle Scholar
  29. 29.
    Campbell EL, Chebib M, Johnston GAR (2004) The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors. Biochem Pharmacol 68:1631–1638CrossRefGoogle Scholar
  30. 30.
    Kottra G, Daniel H (2007) Flavonoid glycosides are not transported by the human Na+/glucose transporter when expressed in Xenopus laevis oocytes, but effectively inhibit electrogenic glucose uptake. J Pharmacol Exp Ther 322:829–835CrossRefGoogle Scholar
  31. 31.
    Picherit C, Dalle M, Neliat G, Lebecque P, Davicco MJ, Barlet JP, Coxam V (2000) Genistein and daidzein modulate in vitro rat uterine contractile activity. J Steroid Biochem 75:201–208CrossRefGoogle Scholar
  32. 32.
    Tao J, Zhang Y, Li SN, Sun WH, Soong TW (2009) Tyrosine kinase-independent inhibition by genistein on spermatogenic T-type calcium channels attenuates mouse sperm motility and acrosome reaction. Cell Calcium 45:133–143CrossRefGoogle Scholar
  33. 33.
    Molokanova E, Kramer RH (2001) Mechanism of inhibition of cyclic nucleotide-gated channel by protein tyrosine kinase probed with genistein. J Gen Physiol 117:219–233CrossRefGoogle Scholar
  34. 34.
    Kusaka M, Sperelakis N (1996) Genistein inhibition of fast Na+ current in uterine leiomyosarcoma cells is independent of tyrosine kinase inhibition. Biochim Biophys Acta 1278:1–4CrossRefGoogle Scholar
  35. 35.
    Coleta M, Campos MG, Cotrim MD, de Lima TCM, da Cunha AP (2008) Assessment of luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res 189:75–82CrossRefGoogle Scholar
  36. 36.
    Suryaprakash P, Prakash V (1995) Interaction of 3′-O-caffeoyl D-quinic acid with multisubunit protein helianthinin. J Biosci 20:531–549CrossRefGoogle Scholar
  37. 37.
    Sastry MCS, Rao MSN (1991) Effect of chemical modification of sunflower 11 S protein on the binding of chlorogenic acid. J Agr Food Chem 39:63–66CrossRefGoogle Scholar
  38. 38.
    Goodenough PW, Kessell S, Lea AGH, Loeffler T (1983) Monophenolase and diphenolase activity from fruit of Malus-pumila. Phytochemistry 22:359–363CrossRefGoogle Scholar
  39. 39.
    Tanaka Y, Uritani I (1977) Purification and properties of phenylalanine ammonia-lyase in cut-injured sweet-potato. J Biochem 81:963–970Google Scholar
  40. 40.
    Spencer CM, Cai Y, Martin R, Gaffney SH, Goulding PN, Magnolato D, Lilley TH, Haslam E (1988) Polyphenol complexation - some thoughts and observations. Phytochemistry 27:2397–2409CrossRefGoogle Scholar
  41. 41.
    Hanlon N, Coldham N, Gielbert A, Kuhnert N, Sauer MJ, Kingi LJ, Ioannides C (2008) Absolute bioavailability and dose-dependent pharmacokinetic behaviour of dietary doses of the chemopreventive isothiocyanate sulforaphane in rat. Brit J Nutr 99:559–564CrossRefGoogle Scholar
  42. 42.
    Manach C, Williamson G, Morand C, Scalbert A, Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81:230S–242SGoogle Scholar
  43. 43.
    Haslam E (1986) Secondary metabolism - fact and fiction. Nat Prod Rep 3:217–249CrossRefGoogle Scholar
  44. 44.
    Firn RD, Jones CG (2003) Natural products - a simple model to explain chemical diversity. Nat Prod Rep 20:382–391CrossRefGoogle Scholar
  45. 45.
    Jones CG, Firn RD (1991) On the evolution of plant secondary chemical diversity. Philos T Roy Soc B 333:273–280CrossRefGoogle Scholar
  46. 46.
    Firn R (2004) Plant intelligence: An alternative point of view. Ann Bot 93:345–351CrossRefGoogle Scholar
  47. 47.
    Kuhnert N (2010) Unraveling the structure of the black tea thearubigins. Arc Biochem Biophys 501:37–51CrossRefGoogle Scholar
  48. 48.
    Kuhnert N, Drynan JW, Obuchowicz J, Witt M, Clifford M (2010) On the chemical characterization of black tea thearubigins using mass spectrometry. Rapid Commun Mass Spetrom 24:3387–3404CrossRefGoogle Scholar
  49. 49.
    Kuhnert N, Müller A, Clifford (2010) Analysis of black tea thearubigins: Evidence for oxidative cascade reactions forming the thearubigins. Food Funct 1:180–199CrossRefGoogle Scholar
  50. 50.
    Drynan JW, Clifford MN, Obuchowicz J, Kuhnert N (2010) The chemistry of low molecular weight black tea polyphenols. Nat Prod Rep 27:417–462CrossRefGoogle Scholar
  51. 51.
    Jaiswal R, Patras MA, Eravuchira PJ, Kuhnert N (2010) Profile and characterization of the chlorogenic acids in green Robusta coffee beans by LC-MSn: Identification of seven new classes of compounds. J Agr Food Chem 58:8722–8737CrossRefGoogle Scholar
  52. 52.
    Kuhnert N, Jaiswal R, Eruvichera P, El-Abassy R, von der Kammer B, Materny M (2010) Scope and limitations of principal component analysis of high resolution LC-MS data: The analysis of the chlorogenic acid fraction in green coffee beans as a case study. Anal Meth. doi: 10.1039/c0ay00512f Google Scholar
  53. 53.
    Jaiswal R, Sovdat T, Vivan F, Kuhnert N (2010) Profiling and characterization by LC-MSn of the chlorogenic acids and hydroxycinnamoylshikimate esters in mate (Ilex paraguariensis). J Agr Food Chem 58:5471–5484CrossRefGoogle Scholar
  54. 54.
    Clifford MN, Kirkpatrick J, Kuhnert N, Roozendaal H, Salgado PR (2008) LC-MSn analysis of the cis isomers of chlorogenic acids. Food Chem 106:379–385CrossRefGoogle Scholar
  55. 55.
    Haslam E (1996) Natural polyphenols (vegetable tannins) as drugs: Possible modes of action. J Nat Prod 59:205–215CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nikolai Kuhnert
    • 1
    Email author
  • Farnoosh Dairpoosh
    • 1
  • Rakesh Jaiswal
    • 1
  • Marius Matei
    • 1
  • Sagar Deshpande
    • 1
  • Agnieszka Golon
    • 1
  • Hany Nour
    • 1
  • Hande Karaköse
    • 1
  • Nadim Hourani
    • 1
  1. 1.School of Engineering and Science, Centre for Nano- and functional materialsJacobs University BremenBremenGermany

Personalised recommendations