Journal of Molecular Modeling

, 25:347 | Cite as

Theoretical study of formate, tartrate, tartronate, and glycolate production from 6-carbon trioxylate intermediate in the citric acid cycle

  • Mehedi Khan
  • Supratik Kar
  • Jing Wang
  • Jerzy LeszczynskiEmail author
Original Paper
Part of the following topical collections:
  1. Zdzislaw Latajka 70th Birthday Festschrift


Reaction pathways of side products (formate, glycolate, and tartronate) from dihydroxyfumarate (DHF) were theoretically investigated as DHF is an intermediate in the process of producing tartrates and oxalate from glyoxylate of the citric acid cycle. The proposed pathways for each reaction were mapped by density functional theory (DFT) calculations. The transitions states were confirmed by analyzing the vibrational frequency and the intrinsic reaction coordinate (IRC) theory. The corresponding reaction activation energy, enthalpy change, Gibb’s free energy change, and rate of reactions were calculated to get a clear picture of the whole reaction pathway. In the whole process, the decarboxylation reaction showed the highest energy barrier of 20–23 kcal/mol. Proton transfer and hydroxylation reactions were almost barrierless. As most of these reactions have very low energy barrier, our findings elucidate the high probability of those reactions under experimental conditions.


Citric acid cycle DFT Formate Glycolate Tartrate Tartronate 


Funding information

This work was jointly supported by NSF and the NASA Astrobiology Program under the NSF Center for Chemical Evolution, CHE1004570. The computation time was provided by the Extreme Science and Engineering Discovery Environment (XSEDE) by National Science Foundation grant number OCI-1053575 and XSEDE award allocation number DMR110088 and by the Mississippi Center for Supercomputer Research.

Supplementary material

894_2019_4240_MOESM1_ESM.docx (185 kb)
ESM 1 (DOCX 184 kb)


  1. 1.
    Kasting J (1993) Earth’s early atmosphere. Science 259:920–926CrossRefGoogle Scholar
  2. 2.
    Orgel LE (1998) The origin of life – how long did it take? Orig Life Evol Biosph 28:91–96CrossRefGoogle Scholar
  3. 3.
    Oparin AI (1924) ProischogdenieZhizni. MoscovskyRobotschii.Google Scholar
  4. 4.
    Oparin AI (1965) Origin of life2nd edn. Dover PublicationGoogle Scholar
  5. 5.
    Miller SL (1953) A production of amino acids under possible primitive earth conditions. Science 117:2CrossRefGoogle Scholar
  6. 6.
    Miller SL (1955) Production of some organic compounds under possible primitive earth conditions. J Am Chem Soc 77:2351–2361CrossRefGoogle Scholar
  7. 7.
    Schwartz W (1967) Sidney W. Fox (Herausgeber), The origin of prebiological systems and of their molecular matrices. XX + 482 S., 110 Abb., 35 Tab, vol 7. Academic Press. $ 8. Z Allg Mikrobiol, New York, London 1965, pp 245–245Google Scholar
  8. 8.
    Cleaves II HJ, ScottAM HFC, Leszczynski J, Sahai N, Hazen R (2012) Mineral-organic interfacial processes: potential roles in the origins of life. Chem Soc Rev 41:5502–5525CrossRefGoogle Scholar
  9. 9.
    Haldane JBS (1929) The origin of life. Ration Annu 148:8Google Scholar
  10. 10.
    MillerSS UHC (1959) Organic coumpound synthesis on primitive earth. Science 130:7CrossRefGoogle Scholar
  11. 11.
    Parker ET, Cleaves HJ, Dworkin JP, Glavin DP, Callahan M, Aubrey A, Lazcano A, Bada JL (2011) Primordial synthesis of amines and amino acids in a 1958 Miller H2S-rich spark discharge experiment. Proc Natl Acad Sci U S A 108:5526–5531CrossRefGoogle Scholar
  12. 12.
    Morowitz HJ (1999) A theory of biochemical organization, metabolic pathways, and evolution. Complexity 4:39–53CrossRefGoogle Scholar
  13. 13.
    QuayleJR FT (1978) Evolutionary aspects of autotrophy. Microbiol Rev 42:251–273Google Scholar
  14. 14.
    Eschenmoser A (2007) The search for the chemistry of life’s origin. Tetrahedron 63:12821–12844CrossRefGoogle Scholar
  15. 15.
    Wächtershäuser G (1990) Evolution of the first metabolic cycles. Proc Natl Acad Sci U S A 87:200–204CrossRefGoogle Scholar
  16. 16.
    Hartman H (1975) Speculations on the origin and evolution of metabolism. J Mol Evol 4:359–370CrossRefGoogle Scholar
  17. 17.
    McFadden BA (1973) Autotrophic CO2 assimilation and the evolution of ribulose diphosphate carboxylase. Bacteriol Rev 37:289–319PubMedPubMedCentralGoogle Scholar
  18. 18.
    Morowitz HJ, Kostelnik JD, Yang J, Cody GD (2000) The origin of intermediary metabolism. Proc Natl Acad Sci U S A 97:7704–7708CrossRefGoogle Scholar
  19. 19.
    Sagi VN, Punna V, Hu F, Meher G, Krishnamurthy R (2012) Exploratory experiments on the chemistry of the “Glyoxylate Scenario”: formation of ketosugars from dihydroxyfumarate. J Am Chem Soc 134:3577–3589CrossRefGoogle Scholar
  20. 20.
    Butch C, Cope ED, Pollet P, Gelbaum L, Krishnamurthy R, Liotta CL (2013) Production of tartrates by cyanide-mediated dimerization of glyoxylate: a potential abiotic pathway to the citric acid cycle. J Am Chem Soc 135:13440–13445CrossRefGoogle Scholar
  21. 21.
    Butch CJ, Wang J, Gu J, Vindas R, Crowe J, Pollet P, Gelbaum L, Leszczynski J, Krishnamurthy R, Liotta CL (2016) pH-controlled reaction divergence of decarboxylation versus fragmentation in reactions of dihydroxyfumarate with glyoxylate and formaldehyde: parallels to biological pathways. J Phys Org Chem 29:352–360CrossRefGoogle Scholar
  22. 22.
    Eschenmoser A (2007) On a hypothetical generational relationship between HCN and constituents of the reductive citric acid cycle. Chem Biodivers 4:554–573CrossRefGoogle Scholar
  23. 23.
    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 functionals. Theor Chem Accounts 120:215–241CrossRefGoogle Scholar
  24. 24.
    Ayala PY, Schlegel HB (1997) A combined method for determining reaction paths, minima, and TS geometries. J Chem Phys 107:375–384Google Scholar
  25. 25.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2018) Gaussian 09, Revision E.01, Inc., Wallingford CT.Google Scholar
  26. 26.
    MarvinView, ChemAxon. 2014, (6.3.0).Google Scholar
  27. 27.
    Walker M, Harvey AJA, Sen A, Dessent CEH (2013) Performance of M06, M06-2X, and M06-HF density functionals for conformationally flexible anionic clusters: M06 functionals perform better than B3LYP for a model system with dispersion and ionic hydrogen-bonding interactions. J Phys Chem A 117:12590–12600CrossRefGoogle Scholar
  28. 28.
    Hohenstein EG, Chill ST, Sherrill CD (2008) Assessment of the performance of the M05 − 2X and M06 − 2X exchange-correlation functionals for noncovalent interactions in biomolecules. J Chem Theory Comput 4:1996–2000CrossRefGoogle Scholar
  29. 29.
    Mennucci B (2012) Polarizable continuum model. Wiley Interdiscip Rev Comput Mol Sci 2:386–404Google Scholar
  30. 30.
    Fukui K (1981) The path of chemical reactions - the IRC approach. Acc Chem Res 14:363–368CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Interdisciplinary Center for Nanotoxicity, Department of Chemistry, Physics and Atmospheric SciencesJackson State UniversityJacksonUSA

Personalised recommendations