Journal of Molecular Modeling

, 25:295 | Cite as

New paths of cyanogenesis from enzymatic-promoted cleavage of β-cyanoglucosides are suggested by a mixed DFT/QTAIM approach

  • Rafael Díaz-Sobac
  • Alma Vázquez-Luna
  • Eduardo Rivadeneyra-Domínguez
  • Juan Francisco Rodríguez-Landa
  • Tomás GuerreroEmail author
  • J. Sergio Durand-NiconoffEmail author
Original Paper


Cyanogenesis is an enzyme-promoted cleavage of β-cyanoglucosides; the release of hydrogen cyanide is believed to produce food poisoning by consumption of certain crops as Cassava (Manihot esculenta Crantz). The production of hydrogen cyanide by some disruption of the plant wall is related to the content of two β-cyanoglucosides (linamarin and lotaustralin) which are stored within the tuber. Some features about the mechanistic bases of these transformations have been published; nevertheless, there are still questions about the exact mechanism, such as the feasibility of a difference in the kinetics of cyanogenesis between both cyanoglucosides. In this work, we have performed a theoretical analysis using DFT and QTAIM theoretical frameworks to propose a feasible mechanism of the observed first step of the enzyme-catalyzed rupture of these glucosides; our results led us to explain the observed difference between linamarin and lotaustralin. Meanwhile, DFT studies suggest that there are no differences between local reactivity indexes of both glucosides; QTAIM topological analysis suggests two important intramolecular interactions which we found to fix the glucoside in such a way that suggests the linamarin as a more reactive system towards a nucleophilic attack, thus explaining the readiness to liberate hydrogen cyanide.


QTAIM DFT Cyanogenesis Linamarase β-Cyanoglucosides Linamarin Lotaustralin Cassava 


Funding information

The authors thank PRODEP academic federal support and Dirección General de Investigaciones – Universidad Veracruzana for funding this work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Jensen NB, Zagrobelny M, Hjernø K et al (2011) Convergent evolution in biosynthesis of cyanogenic defence compounds in plants and insects. Nat Commun 2:1–7. CrossRefGoogle Scholar
  2. 2.
    Mkpong OE, Yan H, Chism G, Sayre RT (1990) Purification, characterization, and localization of linamarase in cassava. Plant Physiol 93:176–181. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bradbury JH, Egan SV, Lynch MJ (1991) Analysis of cyanide in cassava using acid hydrolysis of cyanogenic glucosides. J Sci Food Agric 55:277–290. CrossRefGoogle Scholar
  4. 4.
    Egan SV, Yeoh HH, Bradbury JH (1998) Simple picrate paper kit for determination of the cyanogenic potential of cassava flour. J Sci Food Agric 76:39–48.<39::aid-jsfa947>;2-m CrossRefGoogle Scholar
  5. 5.
    Barrett T, Suresh CG, Tolley SP et al (1995) The crystal structure of a cyanogenic β-glucosidase from white clover, a family 1 glycosyl hydrolase. Structure 3:951–960. CrossRefPubMedGoogle Scholar
  6. 6.
    Rivadeneyra-Domínguez E, Vázquez-Luna A, Díaz-Sobac R et al (2017) Contribution of hippocampal area CA1 to acetone cyanohydrin-induced loss of motor coordination in rats. Neurol (English Ed) 32:230–235. CrossRefGoogle Scholar
  7. 7.
    Yeoh HH, Tatsuma T, Oyama N (1998) Monitoring the cyanogenic potential of cassava: the trend towards biosensor development. TrAC - Trends Anal Chem 17:234–240CrossRefGoogle Scholar
  8. 8.
    Ernesto M, Cardoso AP, Nicala D et al (2002) Persistent konzo and cyanogen toxicity from cassava in northern Mozambique. Acta Trop 82:357–362. CrossRefPubMedGoogle Scholar
  9. 9.
    Madhusudanan M, Menon MK, Ummer K, Radhakrishnanan K (2008) Clinical and etiological profile of tropical ataxic neuropathy in Kerala, South India. Eur Neurol 60:21–26. CrossRefPubMedGoogle Scholar
  10. 10.
    Nzwalo H, Cliff J (2011) Konzo: from poverty, cassava, and cyanogen intake to toxico-nutritional neurological disease. PLoS Negl Trop Dis 5:e1051CrossRefGoogle Scholar
  11. 11.
    Rivadeneyra-Domínguez E, Vázquez-Luna A, Rodríguez-Landa JF, Díaz-Sobac R (2013) Neurotoxic effect of linamarin in rats associated with cassava (Manihot esculenta Crantz) consumption. Food Chem Toxicol 59:230–235. CrossRefPubMedGoogle Scholar
  12. 12.
    Rivadeneyra-Domíngueza E, Vázquez-Luna A, Rodríguez-Landa JF, Díaz-Sobac R (2014) Astandardized extract of Ginkgo biloba prevents locomotion impairment induced by cassava juice in Wistar rats. Front Pharmacol 5:213. CrossRefGoogle Scholar
  13. 13.
    Rivadeneyra-Domínguez E, Rodríguez-Landa JF (2016) Motor impairments induced by microinjection of linamarin in the dorsal hippocampus of Wistar rats. Neurol (English Ed) 31:516–522. CrossRefGoogle Scholar
  14. 14.
    McCarter JD, Stephen Withers G (1994) Mechanisms of enzymatic glycoside hydrolysis. Curr Opin Struct Biol 4:885–892. CrossRefPubMedGoogle Scholar
  15. 15.
    White A, Tull D, Johns K et al (1996) Crystallographic observation of a covalent catalytic intermediate in a β-glycosidase. Nat Struct Biol 3:149–154. CrossRefPubMedGoogle Scholar
  16. 16.
    Bader RFW (1985) Atoms in molecules. Acc Chem Res 18:9–15. CrossRefGoogle Scholar
  17. 17.
    Popelier PLA (2014) The QTAIM perspective of chemical bonding. In: The chemical bond: fundamental aspects of chemical bonding. pp 271–308CrossRefGoogle Scholar
  18. 18.
    Matta CF (2017) On the connections between the quantum theory of atoms in molecules (QTAIM) and density functional theory (DFT): a letter from Richard F. W. Bader to Lou Massa. Struct Chem 28:1591–1597. CrossRefGoogle Scholar
  19. 19.
    Morgenstern A, Wilson T, Miorelli J et al (2015) In search of an intrinsic chemical bond. Comput Theor Chem 1053:31–37. CrossRefGoogle Scholar
  20. 20.
    Bader RFW (2001) The zero-flux surface and the topological and quantum definitions of an atom in a molecule. Theor Chem Accounts 105:276–283. CrossRefGoogle Scholar
  21. 21.
    Bayat A, Fattahi A (2018) Influence of remote intramolecular hydrogen bonding on the acidity of hydroxy-1,4-benzoquinonederivatives: a DFT study. J Phys Org Chem 32:e3919. Accepted m. CrossRefGoogle Scholar
  22. 22.
    Brovarets’ OO, Tsiupa KS, Hovorun DM (2018) Surprising conformers of the biologically important a. T DNA bases pairs: QM/QTAIM proofs. Front Chem 6:8/1–8/11. CrossRefGoogle Scholar
  23. 23.
    Vega-Hissi EG, Tosso R, Enriz RD, Gutierrez LJ (2015) Molecular insight into the interaction mechanisms of amino-​2H-​imidazole derivatives with BACE1 protease: a QM/MM and QTAIM study. Int J Quantum Chem 115:389–397. CrossRefGoogle Scholar
  24. 24.
    Barrera Guisasola EE, Gutiérrez LJ, Salcedo RE et al (2016) Conformational transition of Aβ42inhibited by a mimetic peptide. A molecular modeling study using QM/MM calculations and QTAIM analysis. Comput Theor Chem 1080:56–65. CrossRefGoogle Scholar
  25. 25.
    Dalla Torre G, Mujika JI, Formoso E et al (2018) Tuning the affinity of catechols and salicylic acids towards Al(III): characterization of Al-chelator interactions. Dalton Trans 47:9592–9607. CrossRefPubMedGoogle Scholar
  26. 26.
    Astani EK, Chen NC, Huang YC et al (2017) DFT, QTAIM, and NBO studies on the trimeric interactions in the protrusion domain of a piscine betanodavirus. J Mol Graph Model 78:61–73. CrossRefPubMedGoogle Scholar
  27. 27.
    Hesabi M, Behjatmanesh-Ardakani R (2017) Interaction between anti-cancer drug hydroxycarbamide and boron nitride nanotube: a long-range corrected DFT study. Comput Theor Chem 1117:61–80. CrossRefGoogle Scholar
  28. 28.
    Melendez FJ, Durand-Niconoff JS, Díaz-Sobac R et al (2016) Analysis of the topology of the electron density and the reactivity descriptors of biomolecules with insecticide activity. Theor Chem Accounts 135:1–14. CrossRefGoogle Scholar
  29. 29.
    Bader RFW (1990) Atoms in molecules: a quantum theory. Encycl. Comput. Chem. 1–100Google Scholar
  30. 30.
    Parr RG, Yang W (1995) Density-functional theory of the electronic structure of molecules. Annu Rev Phys Chem 46:701–728. CrossRefPubMedGoogle Scholar
  31. 31.
    Parr RG, Pearson RG (1983) Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc 105:7512–7516. CrossRefGoogle Scholar
  32. 32.
    Pearson RG (1990) Hard and soft acids and bases-the evolution of a chemical concept. Coord Chem Rev 100:403–425. CrossRefGoogle Scholar
  33. 33.
    Gázquez JL, Cedillo A, Vela A (2007) Electrodonating and electroaccepting powers. J Phys Chem A 111:1966–1970. CrossRefPubMedGoogle Scholar
  34. 34.
    Zhan CG, Nichols JA, Dixon DA (2003) Ionization potential, electron affinity, electronegativity, hardness, and electron excitation energy: molecular properties from density functional theory orbital energies. J Phys Chem A 107:4184–4195. CrossRefGoogle Scholar
  35. 35.
    Parr RG, Yang W (1984) Density functional approach to the frontier-electron theory of chemical reactivity. J Am Chem Soc 106:4049–4050. CrossRefGoogle Scholar
  36. 36.
    Yang W, Mortier WJ (1986) The use of global and local molecular parameters for the analysis of the gas-phase basicity of amines. J Am Chem Soc 108:5708–5711. CrossRefPubMedGoogle Scholar
  37. 37.
    Morell C, Grand A, Toro-Labbé A (2005) New dual descriptor for chemical reactivity. J Phys Chem A 109:205–212. CrossRefPubMedGoogle Scholar
  38. 38.
    Morell C, Gázquez JL, Vela A et al (2014) Revisiting electroaccepting and electrodonating powers: proposals for local electrophilicity and local nucleophilicity descriptors. Phys Chem Chem Phys 16:26832–26842. CrossRefPubMedGoogle Scholar
  39. 39.
    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 113:6378–6396. CrossRefGoogle Scholar
  40. 40.
    MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, MA Robb, JR Cheeseman, G Scalmani, V Barone, B Mennucci, GA Petersson, H Nakatsuji, M Caricato, X Li, HP Hratchian, AF Izmaylov, J Bloino, G Zheng, JL Sonnenberg, M Hada, M Ehara, K Toyota, R Fukuda, Haseg JDF (2010) Gaussian09, revision B.01. Gaussian Inc, Wallingford, CTGoogle Scholar
  41. 41.
    Godbout N, Salahub DR, Andzelm J, Wimmer E (1992) Optimization of Gaussian-type basis sets for local spin density functional calculations. Part I. Boron through neon, optimization technique and validation. Can J Chem 70:560–571. CrossRefGoogle Scholar
  42. 42.
    Zhao Y, Truhlar DG (2008) 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 function. Theor Chem Accounts 120:215–241. CrossRefGoogle Scholar
  43. 43.
    Hirshfeld FL (1977) Bonded-atom fragments for describing molecular charge densities. Theor Chim Acta 44:129–138. CrossRefGoogle Scholar
  44. 44.
    Keith TA (2016) AIMAll (version 17.01.25). In: TK Gristmill Softw. Overl. Park. KS, 2016 (available Accessed 27 Aug 2019
  45. 45.
    Liotard DA (1992) Algorithmic tools in the study of semiempirical potential surfaces. Int J Quantum Chem 44:723–741. CrossRefGoogle Scholar
  46. 46.
    Li X, Frisch MJ (2006) Energy-represented direct inversion in the iterative subspace within a hybrid geometry optimization method. J Chem Theory Comput 2:835–839. CrossRefPubMedGoogle Scholar
  47. 47.
    Forslund K, Morant M, Jørgensen B, Olsen CE, Asamizu E, Sato S, Tabata S, Bak S (2004) Biosynthesis of the nitrile glucosides rhodiocyanoside A and D and the cyanogenic glucosides lotaustralin and linamarin in Lotus japonicus. Plant Physiol 135:71–84. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Keresztessy Z, Brown K, Dunn MA, Hughes MA (2001) Identification of essential active-site residues in the cyanogenic β-glucosidase (linamarase) from cassava (Manihot esculenta Crantz) by site-directed mutagenesis. Biochem J 353:199–205. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hughes MA, Brown K, Pancoro A et al (1992) A molecular and biochemical analysis of the structure of the cyanogenic β-glucosidase (linamarase) from cassava (Manihot esculenta Cranz). Arch Biochem Biophys 295:273–279. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Instituto de Ciencias BásicasUniversidad VeracruzanaXalapaMexico
  2. 2.Facultad de Química Farmacéutica BiológicaUniversidad VeracruzanaXalapaMexico
  3. 3.Laboratorio de Neurofarmacología, Instituto de NeuroetologíaUniversidad VeracruzanaXalapaMexico

Personalised recommendations