In Silico Modeling of C1 Metabolism


An integrative computational, in silico, model of C1 metabolism is developed from molecular pathway systems identified from a recent, comprehensive systematic bioinformatics review of C1 metabolism. C1 metabolism is essential for all organisms to provide one-carbon units for methylation and other types of modifications, as well as for nucleic acid, amino acid, and other biomolecule syntheses. C1 metabolism consists of three important molecular pathway systems: 1) methionine biosynthesis, 2) methylation cycle, and 3) formaldehyde detoxification. Each of the three molecular pathway systems is individually modeled using the CytoSolve?  Collaboratory?, a proven and scalable computational systems biology platform for in silico modeling of complex molecular pathway systems. The individual models predict the temporal behavior of formaldehyde, formate, sarcosine, glutathione (GSH), and many other key biomolecules involved in C1 metabolism, which may be hard to measure experimentally. The individual models are then coupled and integrated dynamically using CytoSolve to produce, to the authors’ knowledge, the first comprehensive computational model of C1 metabolism. In silico modeling of the individual and integrated C1 metabolism models enables the identification of the most sensitive parameters involved in the detoxification of formaldehyde. This integrative model of C1 metabolism, giving its systems-based nature, can likely serve as a platform for: 1) generalized research and study of C1 metabolism, 2) hypothesis generation that motivates focused and specific in vitro and in vivo testing in perhaps a more efficient manner, 3) expanding a systems biology understanding of plant bio-molecular systems by integrating other known molecular pathway systems associated with C1 metabolism, and 4) exploring and testing the potential effects of exogenous inputs on the C1 metabolism system.

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Kothandaram, S. , Deonikar, P. , Mohan, M. , Venugopal, V. and Ayyadurai, V. (2015) In Silico Modeling of C1 Metabolism. American Journal of Plant Sciences, 6, 1444-1465. doi: 10.4236/ajps.2015.69144.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Hanson, A.D., Gage, D.A. and Shachar-Hill, Y. (2000) Plant One-Carbon Metabolism and Its Engineering. Trends in Plant Science, 5, 206-213.
[2] Hanson, A.D. and Roje, S. (2001) One-Carbon Metabolism in Higher Plants. Annual Review of Plant Physiology and Plant Molecular Biology, 52, 119-137.
[3] Vanyushin, B.F. (2006) DNA Methylation in Plants: DNA Methylation: Basic Mechanisms. Springer, Berlin, Heidelberg.
[4] Deonikar, P., Kothandaram, S., Mohan, M., Kollin, C., Konecky, P., Olovyanniko, R., Zamore, Z., Carey, B. and Ayyadurai, V.A.S. (2015) Discovery of Key Molecular Pathways of C1 Metabolism and Formaldehyde Detoxification in Maize through a Systematic Bioinformatics Literature Review. Agricultural Sciences, 6, 571-585.
[5] Ayyadurai, V.A.S. and Dewey, C.F. (2011) CytoSolve: A Methodology for Dynamic Integration of Multiple Molecular Pathway Models. Cellular and Molecular Bioengineering, 4, 28-45.
[6] Ayyadurai, V.A.S. (2011) Services-Based Systems Architecture for Modeling the Whole Cell: A Distributed Collaborative Engineering Systems Approach. Communications in Medical and Care Compunetics, 1, 115-168.
[7] Mouillon, J.M., Aubert, S., Bourguignon, J., Gout, E., Douce, R. and Rébeillé, F. (1999) Glycine and Serine Catabolism in Non-Photosynthetic Higher Plant Cells: Their Role in C1 Metabolism. The Plant Journal, 20, 197-205.
[8] Peacock, D. and Boulter, D. (1970) Kinetic Studies of Formate Dehydrogenase. Biochemical Journal, 120, 763-769.
[9] Zhang, W., Tang, L., Sun, H., et al. (2014) C1 Metabolism Plays an Important Role during Formaldehyde Metabolism and Detoxification in Petunia Under Liquid HCHO Stress. Plant Physiology and Biochemistry, 83, 327-336.
[10] Janave, M.T., Ramaswamy, N.K. and Nair, P.M. (1993) Purification and Characterization of Glyoxylatesynthetase from Greening Potato-Tuber Chloroplasts. European Journal of Biochemistry, 214, 889-896.
[11] Ravanel, S., Block, M.A., Rippert, P., et al. (2004) Methionine Metabolism in Plants: Chloroplasts Are Autonomous for de Novo Methionine Synthesis and Can Import S-Adenosylmethionine from the Cytosol. The Journal of Biological Chemistry, 279, 22548-22557.
[12] Chen, L., Chan, S.Y. and Cossins, E.A. (1997) Distribution of Folate Derivatives and Enzymes for Synthesis of 10-Formyltetrahydrofolate in Cytosolic and Mitochondrial Fractions of Pea Leaves. Plant Physiology, 115, 299-309.
[13] Hanson, A.D. and Gregory, J.F. (2011) Folate Biosynthesis, Turnover, and Transport in Plants. Annual Review of Plant Biology, 62, 105-125.
[14] Rébeillé, F., Stephane, R., Jabrin, S., Douce, R., Storozhenko, S., Re, F. and Van Der Straeten, D. (2006) Folates in Plants: Biosynthesis, Distribution, and Enhancement. Physiologia Plantarum, 126, 330-342.
[15] Appling, D.R. (1991) Compartmentation of Folate-Mediated One-Carbon Metabolism in Eukaryotes. The FASEB Journal, 5, 2645-2651.
[16] Neuburger, M., Rébeillé, F., Jourdain, A., Nakamura, S. and Douce, R. (1996) Mitochondria Are a Major Site for Folate and Thymidylate Synthesis in Plants. The Journal of Biological Chemistry, 271, 9466-9472.
[17] Sahr, T., Ravanel, S. and Rébeillé, F. (2005) Tetrahydrofolate Biosynthesis and Distribution in Higher Plants. Biochemical Society Transactions, 33, 758-762.
[18] Rebeille, F., Neuburger, M. and Douce, R. (1994) Interaction between Glycine Decarboxylase, Serine Hydroxymethyltransferase and Tetrahydrofolate Polyglutamates in Pea Leaf Mitochondria. Biochemical Journal, 302, 223-228.
[19] Kim, D.G., Park, T.J., Kim, J.Y. and Cho, Y.D. (1995) Purification and Characterization of S-Adenosylmethionine Synthetase from Soybean (Glycine max) Axes. Journal of Biochemistry and Molecular Biology, 28, 100-106.
[20] Ravanel, S., Gakière, B., Job, D. and Douce, R. (1998) The Specific Features of Methionine Biosynthesis and Metabolism in Plants. Proceedings of the National Academy of Sciences of the United States of America, 95, 7805-7812.
[21] Ravanel, S., Gambonnet, B., Douce, R. and Rébeillé, F. (2003) One-Carbon Metabolism in Plants. Regulation of Tetrahydrofolate Synthesis during Germination and Seedling Development. Plant Physiology, 131, 1431-1439.
[22] James, F., Nolte, K.D. and Hanson, A.D. (1995) Purification and Properties of S-Adenosyl-L-methionine: L-Methionine S-Methyltransferase from Wollastonia biflora Leaves. The Journal of Biological Chemistry, 270, 22344-22350.
[23] Bradbury, L.M.T., Ziemak, M.J., El Badawi-Sidhu, M., Fiehn, O. and Hanson, A.D. (2014) Plant-Driven Repurposing of the Ancient S-Adenosylmethionine Repair Enzyme Homocysteine S-Methyltransferase. Biochemical Journal, 463, 279-286.
[24] Achkor, H., Díaz, M., Fernández, M.R., Biosca, J.A., Parés, X. and Martínez, M.C. (2003) Enhanced Formaldehyde Detoxification by Overexpression of Glutathione-Dependent Formaldehyde Dehydrogenase from Arabidopsis. Plant Physiology, 132, 2248-2255.
[25] Goyer, A., Johnson, T.L., Olsen, L.J., Collakova, E., Shachar-Hill, Y., Rhodes, D. and Hanson, A.D. (2004) Characterization and Metabolic Function of a Peroxisomalsarcosine and Pipecolate Oxidase from Arabidopsis. The Journal of Biological Chemistry, 279, 16947-16953.
[26] Li, R., Moore, M. and King, J. (2003) Investigating the Regulation of One-Carbon Metabolism in Arabidopsis thaliana. Plant and Cell Physiology, 44, 233-241.
[27] Vivancos, P.D., Driscoll, S.P., Bulman, C., Ying, L., Emami, K., Treumann, A., Mauve, C., Noctor, G. and Foyer, C.H. (2011) Perturbations of Amino Acid Metabolism Associated with Glyphosate-Dependent Inhibition of Shikimic Acid Metabolism Affect Cellular Redox Homeostasis and Alter the Abundance of Proteins Involved in Photosynthesis and Photorespiration. Plant Physiology, 157, 256-268.
[28] Diaz, M., Achkor, H., Titarenko, E. and Martinez, M.C. (2003) The Gene Encoding Glutathione-Dependent Formaldehyde Dehydrogenase/GSNO Reductase Is Responsive to Wounding, Jasmonic Acid and Salicylic Acid. FEBS Letters, 543, 136-139.
[29] Kordic, S., Cummins, I. and Edwards, R. (2002) Cloning and Characterization of an S-Formylglutathione Hydrolase from Arabidopsis thaliana. Archives of Biochemistry and Biophysics, 399, 232-238.
[30] Martinez, M.C., Achkor, H., Perssonz, B., Fernandez, M.R., Shafqat, J. and Farres, J. (1996) Arabidopsis Formaldehyde Dehydrogenase Molecular Properties of Plant Class III Alcohol Dehydrogenase Provide Further Insights into the Origins, Structure and Function of Plant Class P and Liver Class I Alcohol Dehydrogenases. European Journal of Biochemistry, 241, 849-857.
[31] Wippermann, U., Fliegmann, J., Bauw, G., Langebartels, C., Maier, K. and Sandermann, H. (1999) Maize Glutathione-Dependent Formaldehyde Dehydrogenase: Protein Sequence and Catalytic Properties. Planta, 208, 12-18.
[32] Koo, A., Nordsletten, D., Umeton, R., Yankama, B., Ayyadurai, S., García-Cardeña, G. and Dewey Jr., C.F. (2013) In Silico Modeling of Shear-Stress-Induced Nitric Oxide Production in Endothelial Cells through Systems Biology. Biophysical Journal, 104, 2295-2306.
[33] Nijhout, H.F., Reed, M.C., Budu, P. and Ulrich, C.M. (2004) A Mathematical Model of the Folate Cycle: New Insights into Folate Homeostasis. The Journal of Biological Chemistry, 279, 55008-55016.
[34] Zhang, Y., Sun, K., Sandoval, F.J., Santiago, K. and Roje, S. (2010) One-Carbon Metabolism in Plants: Characterization of a Plastid Serine Hydroxymethyltransferase. Biochemical Journal, 430, 97-105.
[35] Yokota, A., Kitaoka, S., Miura, K. and Wadano, A. (1985) Reactivity of Glyoxylate with Hydrogen Perioxide and Simulation of the Glycolate Pathway of C3 Plants and Euglena. Planta, 165, 59-67.
[36] Yeo, E. and Wagner, C. (1992) Purification and Properties of Pancreatic Glycine N-Methyltransferase. The Journal of Biological Chemistry, 267, 24669-24674.
[37] Ogawa, H., Gomi, T. and Fujioka, M. (1993) Mammalian Glycine N-Methyltransferases. Comparative Kinetic and Structural Properties of the Enzymes from Human, Rat, Rabbit and Pig Livers. Comparative Biochemistry and Physiology-Part B, Biochemistry, 106, 601-611.
[38] Alekseeva, A.A., Savin, S.S. and Tishkov, V.I. (2011) NAD+-Dependent Formate Dehydrogenase from Plants. Acta Naturae, 3, 38-54.
[39] Kallen, R.G. and Jencks, P. (1966) The Mechanism of the Condensation of Formaldehyde with Tetrahydrofolic Acid. The Journal of Biological Chemistry, 241, 5851-5863.
[40] Havir, E.A. and McHale, N.A. (1989) Enhanced-Peroxidatic Activity in Specific Catalase Isozymes of Tobacco, Barley, and Maize. Plant Physiology, 91, 812-815.
[41] Wlodek, L. (1988) The Reaction of Sulfhydryl Groups with Carbonyl Compounds. Acta Biochimica Polonica, 35, 307-317.
[42] Wippermann, U., Fliegmann, J., Bauw, G., Langebartels, C., Maier, K. and Sandermann, H. (1999) Maize Glutathione-Dependent Formaldehyde Dehydrogenase: Protein Sequence and Catalytic Properties. Planta, 208, 12-18.

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