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Competition between abiogenic Al3+ and native Mg2+, Fe2+ and Zn2+ ions in protein binding sites: implications for aluminum toxicity

  • Todor Dudev
  • Diana Cheshmedzhieva
  • Lyudmila Doudeva
Original Paper
  • 98 Downloads
Part of the following topical collections:
  1. MIB 2017 (Modeling Interactions in Biomolecules VIII)

Abstract

Abiogenic aluminum has been implicated in some health disorders in humans. Protein binding sites containing essential metals (mostly magnesium) have been detected as targets for the “alien” Al3+. However, the acute toxicity of aluminum is very low. Although a substantial body of information has been accumulated on the biochemistry of aluminum, the underlying mechanisms of its toxicity are still not fully understood. Several outstanding questions remain unanswered: (1) Why is the toxicity of aluminum, unlike that of other “alien” metal cations, relatively low? (2) Apart from Mg2+ active centers in proteins, how vulnerable are other essential metal binding sites to Al3+ attack? (3) Generally, what factors do govern the competition between ‘alien” Al3+ and cognate divalent metal cations in metalloproteins under physiologically relevant conditions? Here, we endeavor to answer these questions by studying the thermodynamic outcome of the competition between Al3+ and a series of biogenic metal cations, such as Mg2+, Fe2+ and Zn2+, in model protein binding sites of various structures, compositions, solvent exposure and charge states. Density functional theory calculations were employed in combination with polarizable continuum model computations. For the first time, the presence of different Al3+ soluble species at physiological pH was properly modeled in accordance with experimental observations. The results suggest that a combination of concentration and physicochemical factors renders the Al3+ → M2+ (M = Mg, Fe, Zn) substitution and subsequent metalloenzyme inhibition a low-occurrence event at ambient pH: the more active aluminum species, [Al(H2O)6]3+, presents in very minute quantities at physiological conditions, while the more abundant soluble aluminum hydrate, {[Al(OH)4](H2O)2}, appears to be thermodynamically incapable of substituting for the native cation.

Keywords

DFT calculations Metal selectivity Aluminum toxicity Metalloproteins 

Notes

Acknowledgments

This work was supported by the project Materials Networking H2020-TWINN-2015.The authors declare no competing financial interests.

References

  1. 1.
    Frausto da Silva JJR, Williams RJP (1991) The biological chemistry of the elements. Oxford University Press, OxfordGoogle Scholar
  2. 2.
    Bertini I, Gray B, Lippard SJ, Valentine JS (1994) Bioinorganic chemistry. University Science Books, Mill ValleyGoogle Scholar
  3. 3.
    Bertini I, Sigel A, Sigel H (eds) (2001) Handbook on metalloproteins. Dekker, New YorkGoogle Scholar
  4. 4.
    Lippard SJ, Berg JM (1994) Principles of bioinorganic chemistry. University Science Books, Mill ValleyGoogle Scholar
  5. 5.
    Christianson DW, Cox JD (1999) Catalysis by metal-activated hydroxide in zinc and manganese metalloenzymes. Annu Rev Biochem 68:33–77CrossRefGoogle Scholar
  6. 6.
    Uversky VN, Kretsinger RH, Permyakov EA (eds) (2013) Encyclopedia of metalloproteins. Springer, New YorkGoogle Scholar
  7. 7.
    Williams RJP (1997) The natural selection of the chemical elements. Cell Mol Life Sci 53:816–829CrossRefGoogle Scholar
  8. 8.
    Zatta P, Lucchini R, van Rensburg SJ, Taylor A (2003) The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Brain Res Bull 62:15–28CrossRefGoogle Scholar
  9. 9.
    Martin R (1986) The chemistry of aluminum as related to biology and medicine. Clin Chem 32:1797–1806Google Scholar
  10. 10.
    Hartwig A (2001) Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signaling 3:625–634CrossRefGoogle Scholar
  11. 11.
    Hartwig A, Asmuss M, Blessing H, Hofmann S, Jahnke G, Khandelwal S, Polzer A, Burkle A (2002) Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability. Food Chem Toxicol 40:1179–1184CrossRefGoogle Scholar
  12. 12.
    MacDonald TL, Martin RB (1988) Aluminum ion in biological systems. Trends Biochem Sci 13:15–19CrossRefGoogle Scholar
  13. 13.
    Exley C (2003) A biogeochemical cycle for aluminium? J Inorg Biochem 97:1–7CrossRefGoogle Scholar
  14. 14.
    Exley C (2013) Aluminum in biological systems. In: Uversky VN, Kretsinger RH, Permyakov EA (eds) Encyclopedia of metalloproteins. Springer, New York, pp 33–34CrossRefGoogle Scholar
  15. 15.
    Martin RB (1994) Aluminum: a neurotoxic product of acid rain. Acc Chem Res 27:204–210CrossRefGoogle Scholar
  16. 16.
    Fan JF, He LJ, Liu J, Tang M (2010) Investigation on the micro-mechanisms of Al3+ interfering the reactivities of aspartic acid and its biological processes with Mg2+. J Mol Model 16:1639–1650CrossRefGoogle Scholar
  17. 17.
    Rezabal E, Mercero JM, Lopez X, Ugalde JM (2007) Protein side chains facilitate Mg/Al exchange in model protein binding sites. ChemPhysChem 8:2119–2124CrossRefGoogle Scholar
  18. 18.
    Rezabal E, Mercero JM, Lopez X, Ugalde JM (2007) A theoretical study of the principles regulating the specificity for Al(III) against Mg(II) in protein cavities. J Inorg Biochem 101:1192–1200CrossRefGoogle Scholar
  19. 19.
    Rezabal E, Mercero JM, Lopez X, Ugalde JM (2006) A study of the coordination shell of aluminum(III) and magnesium(II) in model protein environments: thermodynamics of the complex formation and metal exchange reactions. J Inorg Biochem 100:374–384CrossRefGoogle Scholar
  20. 20.
    Kiss T, Hollosi M (2001) In: Exley C (ed) Aluminium and Alzheimer’s disease. Amsterdam, ElsevierGoogle Scholar
  21. 21.
    Kiss T, Gajda-Schrantz K, Zatta PF (2006) In: Sigel A, Sigel H, Sigel R (eds) Neurodegenerative diseases and metal ions. Wiley, LondonGoogle Scholar
  22. 22.
    Shannon RD (1976) Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallogr Sect A Cryst Phys Diffr Theor Gen Crystallogr 32:751–767CrossRefGoogle Scholar
  23. 23.
    Leonard A, Gerber GB (1988) Mutagenicity, carcinogenicity and teratogenicity of aluminium. Mutat Res 196:247–257CrossRefGoogle Scholar
  24. 24.
    Kavitha AV, Jagadeesan G (2006) Role of Tribulus terrestris (Linn.) (Zygophyllacea) against mercuric chloride induced nephrotoxicity in mice, Mus musculus (Linn.). J Environ Biol 27:397–400Google Scholar
  25. 25.
    Martin RB (1991) Fe3+ and Al3+ hydrolysis equilibria. Cooperativity in Al3+ hydrolysis reactions. J Inorg Biochem 44:141–147CrossRefGoogle Scholar
  26. 26.
    Baes CF, Mesmer RE (1976) The hydrolysis of cations. Wiley, New YorkGoogle Scholar
  27. 27.
    D’Haese PC (2013) Aluminum, biological effects. In: Uversky VN, Kretsinger RH, Permyakov EA (eds) Encyclopedia of metalloproteins. Springer, New York, pp 47–53CrossRefGoogle Scholar
  28. 28.
    Dudev T, Lim C (2010) Factors governing the Na+ vs K+ selectivity in sodium ion channels. J Am Chem Soc 132:2321–2332CrossRefGoogle Scholar
  29. 29.
    Dudev T, Lim C (2011) Competition between Li+ and Mg2+ in Metalloproteins. Implications for lithium therapy. J Am Chem Soc 133:9506–9951CrossRefGoogle Scholar
  30. 30.
    Dudev T, Lim C (2012) Competition among Ca2+, Mg2+, and Na+ for model ion channel selectivity filters: determinants of ion selectivity. J Phys Chem B 116:10703–10714CrossRefGoogle Scholar
  31. 31.
    Dudev T, Lim C (2013) Importance of metal hydration on the selectivity of Mg2+ versus Ca2+ in magnesium ion channels. J Am Chem Soc 135:17200–17208CrossRefGoogle Scholar
  32. 32.
    Dudev T, Lim C (2015) Ion selectivity in the selectivity filters of acid-sensing ion channels. Sci Rep 5:7864CrossRefGoogle Scholar
  33. 33.
    Dudev T, Mazmanian K, Lim C (2016) Factors controlling the selectivity for Na+ over Mg2+ in sodium transporters and enzymes. Phys Chem Chem Phys 18:16986–16997CrossRefGoogle Scholar
  34. 34.
    Nikolova V, Angelova S, Markova N, Dudev T (2016) Gallium as a therapeutic agent: a thermodynamic evaluation of the competition between Ga3+ and Fe3+ ions in metalloproteins. J Phys Chem B 120:2241–2248CrossRefGoogle Scholar
  35. 35.
    Dudev T, Nikolova V (2016) Determinants of Fe2+ over M2+ (M = mg, Mn, Zn) selectivity in non-Heme iron proteins. Inorg Chem 55:12644–12650CrossRefGoogle Scholar
  36. 36.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefGoogle Scholar
  37. 37.
    Dudev T, Cowan JA, Lim C (1999) Competitive binding in magnesium coordination chemistry: water versus ligands of biological interest. J Am Chem Soc 121:7665–7673CrossRefGoogle Scholar
  38. 38.
    Jernigan R, Raghunathan G, Bahar I (1994) Characterization of interactions and metal-ion binding sites in proteins. Curr Opin Struct Biol 4:256–263CrossRefGoogle Scholar
  39. 39.
    Rulisek L, Vondrasek JJ (1998) Coordination geometries of selected transition metal ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in metalloproteins. Inorg Biochem 71:115–127CrossRefGoogle Scholar
  40. 40.
    Marcus Y (1988) Ionic radii in aqueous solutions. Chem Rev 88:1475–1498CrossRefGoogle Scholar
  41. 41.
    Dudev M, Wang J, Dudev T, Lim C (2006) Factors governing the metal coordination number in metal complexes from Cambridge structural database analyses. J Phys Chem B 110:1889–1895CrossRefGoogle Scholar
  42. 42.
    Costas M, Mehn MP, Que Jr L (2004) Dioxygen activation at mononuclear Nonheme iron active sites: enzymes, models, and intermediates. Chem Rev 104:939–986CrossRefGoogle Scholar
  43. 43.
    Cotton FA, Wilkinson G (1980) Advanced inorganic chemistry. Wiley, New YorkGoogle Scholar
  44. 44.
    Zhao Y, Truhlar DG (2006) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Accounts 120:215–241CrossRefGoogle Scholar
  45. 45.
    Frisch MJ, Trucks GW, Schlegel HB et al (2009) Gaussian 09. Gaussian Inc., Wallingford, CTGoogle Scholar
  46. 46.
    Li L, Li C, Zhang Z, Alexov E (2013) On the dielectric constant of proteins: smooth dielectric function for macromolecular modeling and its implementation in DelPhi. J Chem Theory Comput 9:2126–2136CrossRefGoogle Scholar
  47. 47.
    Mertz EL, Krishtalik LI (2000) Low dielectric response in enzyme active site. Proc Natl Acad Sci USA 97:2081–2086CrossRefGoogle Scholar
  48. 48.
    Zheng J (2014) MSc Thesis, University of MinnesotaGoogle Scholar
  49. 49.
    Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396CrossRefGoogle Scholar
  50. 50.
    Dudev T, Lim C (2009) Determinants of K+ vs Na+ selectivity in potassium channels. J Am Chem Soc 131:8092–8101CrossRefGoogle Scholar
  51. 51.
    Hay MB, Myneni SCB (2003) Geometric and electronic structure of the aqueous Al(H2O)6 3+ complex. J Phys Chem A 112:10595–10603CrossRefGoogle Scholar
  52. 52.
    Dudev T, Lim C (2006) A DFT/CDM study of metal-carboxylate interactions in Metalloproteins: factors governing the maximum number of metal-bound carboxylates. J Am Chem Soc 128:1553–1561CrossRefGoogle Scholar
  53. 53.
    Sham TK, Hastings JB, Perlman ML (1980) Structure and dynamic behavior of transition-metal ions in aqueous solution: an EXAFS study of electron-exchange reactions. J Am Chem Soc 102:5904–5906CrossRefGoogle Scholar
  54. 54.
    Kuppuraj G, Dudev M, Lim C (2009) Factors governing metal–ligand distances and coordination geometries of metal complexes. J Phys Chem B 113:2952–2960CrossRefGoogle Scholar
  55. 55.
    Harding MM (1999) The geometry of metal–ligand interactions relevant to proteins. Acta Cryst D55:1432–1443Google Scholar
  56. 56.
    Fuxreiter M, Bocskei Z, Szeibert A, Szabo E, Dallmann G, Naray-Szabo G, Asboth B (1997) Role of electrostatics at the catalytic metal binding site in xylose isomerase action: Ca21-inhibition and metal competence in the double mutant D254E/D256E. Proteins Struct Funct Genet 28:183–193CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Chemistry and PharmacySofia UniversitySofiaBulgaria
  2. 2.Rostislaw Kaischew Institute of Physical ChemistryBulgarian Academy of SciencesSofiaBulgaria

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