DFT study of the mechanism of the reaction of aminoguanidine with methylglyoxal

  • Christian Solís-Calero
  • Joaquín Ortega-CastroEmail author
  • Alfonso Hernández-Laguna
  • Francisco Muñoz
Original Paper
Part of the following topical collections:
  1. Topical Collection QUITEL 2013


We have studied the mechanism of the reaction between aminoguanidine (AG) and methylglyoxal (MG) by carrying out Dmol3/DFT calculations, obtaining intermediates, transition-state structures, and free-energy profiles for all of the elementary steps of the reaction. Designed models included explicit water solvent, which forms hydrogen-bond networks around the reactants and intermediate molecules, facilitating intramolecular proton transfer in some steps of the reaction mechanism. The reaction take place in four steps, namely: (1) formation of a guanylhydrazone–acetylcarbinol adduct by condensation of AG and MG; (2) dehydration of the adduct; (3) formation of an 1,2,4-triazine derivative by ring closure; and (4) dehydration with the formation of 5-methyl 3-amino-1,2,4-triazine as the final product. From a microkinetic point of view, the first dehydration step was found to be the rate-determining step for the reaction, with the reaction having an apparent activation energy of 12.65 kcal mol−1. Additionally, some analogous structures of intermediates and transition states for the reaction between AG and 2,3-dicarbonyl-phosphatidylethanolamine, a possible intermediate in Amadori-glycated phosphatidylethanolamine (Amadori-PE) autooxidation, were obtained to evaluate the reaction above a phosphatidylethanolamine (PE) surface. Our results are in agreement with experimental results obtaining by other authors, showing that AG is efficient at trapping dicarbonyl compounds such as methylglyoxal, and by extension these compounds joined to biomolecules such as PE in environments such as surfaces and their aqueous surroundings.


DFT calculations Methylglyoxal Aminoguanidine 1,2,3-triazines AGEs Phosphatidylethanolamine 



This work was funded by the Spanish Government in the framework of project CTQ2008-02207/BQU. One of us (C. S-C) wishes to acknowledge a MAE-AECI fellowship from the Spanish Ministry of Foreign Affairs and Cooperation. The authors are grateful to Centro de Cálculo de Computación de Galicia (CESGA), and the Centro de Cálculo de Computación de Cataluña (CESCA), for access to their computational facilities.


  1. 1.
    Goh SY, Cooper ME (2008) J Clin Endocrinol Metab 93:1143–1152CrossRefGoogle Scholar
  2. 2.
    Monnier VM (2003) Arch Biochem Biophys 419:1–15CrossRefGoogle Scholar
  3. 3.
    Saraiva MA, Borges CM, Florêncio MH (2012) Eur J Mass Spectrom 18:385–397CrossRefGoogle Scholar
  4. 4.
    Thornalley PJ (2003) Arch Biochem Biophys 419:31–40CrossRefGoogle Scholar
  5. 5.
    Stadler K, Jenei V, Somogyi A, Jakus J (2005) Diabetes Metab Res Rev 21:189–196CrossRefGoogle Scholar
  6. 6.
    Szabó C, Ferrer-Sueta G, Zingarelli B, Southan GJ, Salzman AL, Radi R (1997) J Biol Chem 272:9030–9036CrossRefGoogle Scholar
  7. 7.
    Nilsson BO (1999) Inflamm Res 48:509–515CrossRefGoogle Scholar
  8. 8.
    Ortega-Castro J, Adrover M, Frau J, Salvà A, Donoso J, Muñoz F (2010) J Phys Chem A 114:4634–4640CrossRefGoogle Scholar
  9. 9.
    Adrover M, Vilanova B, Frau J, Muñoz F, Donoso J (2009) Amino Acids 36:437–448CrossRefGoogle Scholar
  10. 10.
    Adrover M, Vilanova B, Muñoz F, Donoso J (2007) Int J Chem Kinet 39:154–167CrossRefGoogle Scholar
  11. 11.
    Adrover M, Vilanova B, Muñoz F, Donoso J (2005) Chem Biodivers 2:964–975CrossRefGoogle Scholar
  12. 12.
    Voziyan PA, Hudson BG (2005) Cell Mol Life Sci 62:1671–1681CrossRefGoogle Scholar
  13. 13.
    Adrover M, Vilanova B, Frau J, Muñoz F, Donoso J (2008) Bioorg Med Chem 16:5557–5569CrossRefGoogle Scholar
  14. 14.
    Ortega-Castro J, Frau J, Casasnovas R, Fernández D, Donoso J, Muñoz F (2012) J Phys Chem A 116:2916–2971CrossRefGoogle Scholar
  15. 15.
    Ortega-Castro J, Adrover M, Frau J, Donoso J, Muñoz F (2009) Chem Phys Lett 475:277–284CrossRefGoogle Scholar
  16. 16.
    Ortega-Castro J, Adrover M, Frau J, Donoso J, Muñoz F (2008) Chem Phys Lett 465:120–125CrossRefGoogle Scholar
  17. 17.
    Leovac VM, Joksovic MD, Divjakovic V, Jovanovic LS, Saranovic Z, Pevec A (2007) J Inorg Biochem 101:1094–1097CrossRefGoogle Scholar
  18. 18.
    Kazachkov M, Chen K, Babiy S, Yu PH (2007) J Pharmacol Exp Ther 322:1201–1207CrossRefGoogle Scholar
  19. 19.
    Webster J, Urban C, Berbaum K, Loske C, Alpar A, Gärtner U, de Arriba SG, Arendt T, Münch G (2005) Neurotox Res 7:95–101CrossRefGoogle Scholar
  20. 20.
    Agalou S, Karachalias N, Dawnay AB, Thornalley PJ (2002) Int Congr Ser 1245:513–515CrossRefGoogle Scholar
  21. 21.
    Thornalley PJ, Yurek-George A, Argirov OK (2000) Biochem Pharmacol 60:55–65CrossRefGoogle Scholar
  22. 22.
    Lo TW, Selwood T, Thornalley PJ (1994) Biochem Pharmacol 48:1865–1870CrossRefGoogle Scholar
  23. 23.
    Hirsch J, Petrakova E, Feather MS (1992) Carbohydr Res 232:125–130CrossRefGoogle Scholar
  24. 24.
    Hirsch J, Baynes JW, Blackledge JA, Feather MS (1991) Carbohydr Res 220:5–7CrossRefGoogle Scholar
  25. 25.
    Richard JP (1993) Biochem Soc Trans 21:549–553Google Scholar
  26. 26.
    Thornalley PJ (1993) Mol Aspects Med 14:287–371CrossRefGoogle Scholar
  27. 27.
    Brownlee M (2001) Nature 414:813–820CrossRefGoogle Scholar
  28. 28.
    Lo TW, Westwood ME, McLellan AC, Selwood T, Thornalley PJ (1994) J Biol Chem 269:32299–32305Google Scholar
  29. 29.
    Turk Z (2010) Physiol Res 59:147–156Google Scholar
  30. 30.
    Thornalley PJ (2007) Novartis Found Symp 285:229–243CrossRefGoogle Scholar
  31. 31.
    Shoji N, Nakagawa K, Asai A, Fujita I, Hashiura A, Nakajima Y, Oikawa S, Miyazawa T (2010) J Lipid Res 51:2445–2453CrossRefGoogle Scholar
  32. 32.
    Nagai R, Ikeda K, Higashi T, Sano H, Jinnouchi Y, Araki T, Horiuchi S (1997) Biochem Biophys Res Commun 234:167–172CrossRefGoogle Scholar
  33. 33.
    Smith PR, Thornalley PJ (1992) Eur J Biochem 210:729–739CrossRefGoogle Scholar
  34. 34.
    Breitling-Utzmann CM, Unger A, Friedl DA, Lederer MO (2001) Arch Biochem Biophys 391:245–254CrossRefGoogle Scholar
  35. 35.
    Delley B (2000) J Chem Phys 113:7756–7764CrossRefGoogle Scholar
  36. 36.
    Delley B (1996) J Phys Chem 100:6107–6110CrossRefGoogle Scholar
  37. 37.
    Delley B (1990) J Chem Phys 92:508–517CrossRefGoogle Scholar
  38. 38.
    Perdew JP, Burke K, Ernzerhof M (1996) Phys Rev Lett 77:3865–3868CrossRefGoogle Scholar
  39. 39.
    Perdew JP, Chevary JA, Vosko SH, Jackson KA, Pederson MR, Singh DJ, Fiolhais C (1992) Phys Rev B 46:6671–6687CrossRefGoogle Scholar
  40. 40.
    Santra B, Michaelides A, Scheffler M (2007) J Chem Phys 127(18):184104CrossRefGoogle Scholar
  41. 41.
    Lee CS, Hwang TS, Wang Y, Peng SM, Hwang CS (1996) J Phys Chem 100:2934–2941CrossRefGoogle Scholar
  42. 42.
    Wang ZG, Zeng QD, Luan YB, Wu XJ, Wan LJ, Wang C, Lee GU, Yin SX, Yang JL, Bai CL (2003) J Phys Chem B 107:13384–13388CrossRefGoogle Scholar
  43. 43.
    Lin TT, Zhang WD, Huang JC, He CB (2005) J Phys Chem B 109:13755–13760CrossRefGoogle Scholar
  44. 44.
    Matsuzawa N, Seto J, Dixon DA (1997) J Phys Chem A 101:9391–9398CrossRefGoogle Scholar
  45. 45.
    Andzelm J, Govind N, Fitzgerald G, Maiti A (2003) Int J Quantum Chem 91:467–473CrossRefGoogle Scholar
  46. 46.
    Delley B (2006) Mol Simul 32:117–123CrossRefGoogle Scholar
  47. 47.
    Klamt A, Schüürmann G (1993) J Chem Soc Perkin Trans 2:799–805CrossRefGoogle Scholar
  48. 48.
    Andzelm J, Kölmel C, Klamt A (1995) J Chem Phys 103:9312–9320CrossRefGoogle Scholar
  49. 49.
    Axson JL, Takahashi K, De Haan DO, Vaida V (2010) Proc Natl Acad Sci U S A 107:6687–6692CrossRefGoogle Scholar
  50. 50.
    Halgren TA, Lipscomb WN (1977) Chem Phys Lett 49:225–232CrossRefGoogle Scholar
  51. 51.
    Elder M, Hitchcock P, Mason R, Shipley GG (1977) Proc R Soc London A 354:157–170CrossRefGoogle Scholar
  52. 52.
    Bharatam PV, Iqbal P, Malde A, Tiwari R (2004) J Phys Chem A 108:10509–10517CrossRefGoogle Scholar
  53. 53.
    Bharatam PV, Iqbal P (2006) J Comput Chem 27:334–343CrossRefGoogle Scholar
  54. 54.
    Solis-Calero C, Ortega-Castro J, Hernández-Laguna A, Muñoz F (2012) Theor Chem Accounts 131:1263–1275CrossRefGoogle Scholar
  55. 55.
    Solis-Calero C, Ortega-Castro J, Muñoz F (2010) J Phys Chem B 114:15879–15885CrossRefGoogle Scholar
  56. 56.
    Salvà A, Donoso J, Frau J, Muñoz F (2003) J Phys Chem A 107:9409–9414CrossRefGoogle Scholar
  57. 57.
    Kalapos MP (1999) Toxicol Lett 110:145–175CrossRefGoogle Scholar
  58. 58.
    Schauestein E, Esterbauer H, Zollner H (1980) α-Dicarbonyls. In: Aldehydes in biological systems. Pion, LondonGoogle Scholar
  59. 59.
    Szent-Györgyi A, McLaughlin JA (1975) Proc Natl Acad Sci USA 72:1610–1611Google Scholar
  60. 60.
    Phucho T, Nongpiur A, Tumtin S, Nongrum R, Myrboh B, Nonghlaw RL (2008) Arkivoc XV:79–87Google Scholar
  61. 61.
    Leoncini G (1979) Ital J Biochem 28:285–294Google Scholar
  62. 62.
    Gokhale MY, Kearney WR, Kirsch LE (2009) AAPS PharmSciTech 10:317–328CrossRefGoogle Scholar
  63. 63.
    Gokhale MY, Kirsch LE (2009) J Pharm Sci 98:4616–4628CrossRefGoogle Scholar
  64. 64.
    Liao RZ, Ding WJ, Yu JG, Fang WH, Liu RZ (2008) J Comput Chem 29:1919–1929CrossRefGoogle Scholar
  65. 65.
    Baldwin JE (1976) J Chem Soc Chem Commun 18:734–736CrossRefGoogle Scholar
  66. 66.
    Neunhoeffer H, Wiley PF (2009) The chemistry of heterocyclic compounds. Vol 33: The chemistry of 1,2,3-triazines and 1,2,4-triazines, tetrazines, and pentazin. Wiley-Interscience, HobokenGoogle Scholar
  67. 67.
    Araki A, Glomb MA, Takahashi M, Monnier VM (1998) Determination of dicarbonyl compounds as aminotriazines during the Maillard reaction and in vivo detection in aminoguanidine-treated rats. In: O’Brien J, Nursten HE, Crabbe MJ, Ames JM (eds) The Maillard reaction in foods and medicine. RSC, CambridgeGoogle Scholar
  68. 68.
    Abdel-Rahman RM, Makki MST, Ali TE, Ibrahim MA (2010) Eur J Chem 1:236–245CrossRefGoogle Scholar
  69. 69.
    Ali TE (2009) Eur J Med Chem 44:4539–4546CrossRefGoogle Scholar
  70. 70.
    Ali TE (2009) Eur J Med Chem 44:4385–4392CrossRefGoogle Scholar
  71. 71.
    Eicher T, Hauptmann S (2003) The chemistry of heterocycles. Wiley-VCH, WeinheimGoogle Scholar
  72. 72.
    Krizner HE, De Haan DO, Kua J (2009) J Phys Chem A 113:6994–7001CrossRefGoogle Scholar
  73. 73.
    Nemet I, Vikic-Topic D, Varga-Defterdarovic L (2004) Bioorg Chem 32:560–570CrossRefGoogle Scholar
  74. 74.
    Rahbar S, Figarola JL (2003) Arch Biochem Biophys 419:63–79CrossRefGoogle Scholar
  75. 75.
    Brownlee M, Vlassara H, Kooney A, Ulrich U, Cerami A (1986) Science 232:1629–1632CrossRefGoogle Scholar
  76. 76.
    Wang Z, Jiang Y, Liu N, Ren L, Zhu Y, An Y, Chen D (2012) Atherosclerosis 221:387–396CrossRefGoogle Scholar
  77. 77.
    Nagai R, Ikeda K, Kawasaki Y, Sano H, Yoshida M, Araki T, Ueda S, Horiuchi S (1998) FEBS Lett 425:355–360CrossRefGoogle Scholar
  78. 78.
    Ikeda K, Higashi T, Sano H, Jinnouchi Y, Yoshida M, Araki T, Ueda S, Horiuchi S (1996) Biochemistry 35:8075–8083CrossRefGoogle Scholar
  79. 79.
    Pamplona R, Requena JR, Portero-Otín M, Prat J, Thorpe SR, Bellmunt MJ (1998) Eur J Biochem 255:685–689CrossRefGoogle Scholar
  80. 80.
    Teissié J, Prats M, Soucaille P, Tocanne JF (1985) Proc Natl Acad Sci USA 82:3217–3221Google Scholar
  81. 81.
    Nagle JF, Tristram-Nagle S (1983) J Membr Biol 74:1–14CrossRefGoogle Scholar
  82. 82.
    Alekseyev VV, Lagoda IV, Yakimovich SI, Yegorova MB (2010) Chem Heterocycl Compd 46:971–982CrossRefGoogle Scholar
  83. 83.
    Suits F, Pitman MC, Feller SE (2005) J Chem Phys 122:244714CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Christian Solís-Calero
    • 1
  • Joaquín Ortega-Castro
    • 1
    Email author
  • Alfonso Hernández-Laguna
    • 2
  • Francisco Muñoz
    • 1
  1. 1.Departament de QuímicaInstitut d’Investigació en Ciències de la Salut (IUNICS)Palma de MallorcaSpain
  2. 2.Instituto Andaluz de Ciencias de la Tierra (CSIC-UGR)GranadaSpain

Personalised recommendations