Boris Kholodenko

Boris Kholodenko is SFI Stokes Professor of Systems Biology at Systems Biology Ireland and Conway Institutes, University College Dublin, Ireland and Adjunct Professor at Thomas Jefferson University, Philadelphia, USA. His group developed the first systems biology model of the Epidermal Growth Factor Receptor signalling pathway and predicted oscillations in MAPK cascades, bistability and travelling waves of protein phosphorylation. Current studies in his laboratory are aimed to understand cellular information transfer and cell-fate decisions governed by the spatiotemporal dynamics of signaling and gene networks.

Research Interests

Experimental and theoretical Systems Biology; Spatiotemporal dynamics of cellular networks; Cancer research

The past decades have witnessed a remarkable progress in the deciphering of the genomes of several species and an explosive growth of biological tools and methods for the investigation of the structure and functional interactions of cellular macromolecules. Yet, a significant challenge confronts biology in the New Millennium. The challenge is an increasing gap between the amount of biochemical and molecular genetic information and our understanding of the implication of these data for the cell system function. The focus of my research group is to integrate the molecular and cell systems levels of analysis to understand and model the behavior of living cells quantitatively. The calculation of the behavior of living cells as the function of nonlinear interactions within and across metabolic, signaling and gene networks can be seen as one of the most important goals of computational cell biology. To this end we employ a novel interdisciplinary approach combining quantitative biological experiments and advanced mathematical, computer and physical analyses.

Selected Publications

  1. Ataullakhanov, F.I., Vitvitsky, V.M., Zhabotinsky, A.M., Pichugin, A.V., Platonova, O.V., Kholodenko, B.N. & Ehrlich, L.I. (1981) The regulation of glycolysis in human erythrocytes. The dependence of the glycolytic flux on the ATP concentration. Eur. J. Biochem.115, 359-365.

  2. Dibrov, B.F., Zhabotinsky, A.M. & Kholodenko, B.N. (1982) Dynamic stability of steady states and static stabilization in unbranched metabolic pathways J. Math. Biol. 15,51-63.

  3. Kholodenko, B.N. (1983) A model of energy metabolism of erythrocytes. Scale invariance of regulatory characteristics. In: Mathematical Modeling in Immunology and Medicine. North-Holl. Publ. Comp. p.311-318.

  4. Kholodenko, B.N. (1983) Power law approximation and similarity properties of metabolic regulatory characteristics. Biophysics (Moscow) 28, 674-681 (Engl. transl. 28, 716-724).

  5. Kholodenko, B.N. (1984) Control of mitochondrial oxidative phosphorylation. J. theor. Biol. 107, 179-188.

  6. Kholodenko, B., Zilinskiene V., Borutaite V., Ivanoviene L., Toleikis A. & Praskevicius A. (1987) The role of adenine nucleotide translocator in regulation of oxidative phosphorylation in heart mitochondria. FEBS Lett. 223,247-250.

  7. Kholodenko, B.N.(1987) Degree of stability of a metabolic chain with one feedback loop. Biophysics (Moscow) 32, 424-428 (Engl. transl. 32, 459-464).

  8. Kholodenko B.N.(1988) Control of molecular transformations in multienzyme systems: quantitative theory of metabolic regulation. Mol. Biol.(Moscow) 22, 1238-1256. (Engl. transl. 22, 990-1005).

  9. Kholodenko, B.N. (1988) How do external parameters control fluxes and concentrations of metabolites? An additional relationship in the theory of metabolic control. FEBS Lett. 232,383-386.

  10. Borutaite, V., Mildaziene, V., Ivanoviene, L., Kholodenko, B., Toleikis, A. & Praskevicius, A. (1989) The role of long-chain acyl-CoA in the damage of oxidative phosphorylation of heart mitochondria. FEBS Lett. 243, 264-266.

  11. Kholodenko, B.N. (1990/1991) Metabolic control theory. New relationships for determining control coefficients of enzymes and response coefficients of system variables. J. Nonlinear Biology, 1, 107-126.

  12. Kholodenko, B.N. (1991) Modern Theory of Metabolic Regulation. Moscow, VINITI PRESS, 97 pp. (In Russian).

  13. Kholodenko, B.N. (1991) Kinetic models of coupling between proton translocation and ATP syntheshs/hydrolysis by FoF1-ATPases. J. Chem. Biochem. Kinetics 1, 141-150.

  14. Kholodenko, B.N., Lyubarev, A.E. & Kurganov, B.I. (1992) Control of the metabolic flux in the system with high enzyme concentrations and moiety-conserved cycles. The sum of the flux control coefficients can drop significantly below unity. Eur. J. Biochem. 210, 147-153.

  15. Kholodenko, B.N. (1993) Kinetic models of coupling between H and Na-translocation and ATP synthesis/hydrolysis by FoF1-ATPases. Can a cell utilize both ??H+ and ??Na+ for the ATP synthesis under in vivo conditions using the same enzyme? J.Bioenerg.Biomembr. 25, 285-295.

  16. Van Dam, K., Van der Vlag, J., Kholodenko, B.N. & Westerhoff, H.V. (1993) The sum of the flux control coefficients of all enzymes on the flux through a group-transfer pathway can be as high as two. Eur. J. Biochem. 212, 791-799.

  17. Kholodenko, B.N. & Westerhoff, H.V. (1993) Metabolic channelling and control of the flux. FEBS Lett. 320,71-74.

  18. Kholodenko, B.N. & Demin, O.V., Westerhoff H.V. (1993) "Channelled" pathways can be more sensitive to specific regulatory signals. FEBS Lett. 320,75-78.

  19. Kholodenko, B.N., Cascante, M. & Westerhoff, H.V. (1993) Dramatic changes in control properties that accompany channelling and metabolite sequestration. FEBS Lett 336, 381-384.

  20. Kholodenko, B.N. (1993) Control theory of "nonclassical" enzyme system and methods for the study of metabolic channeling. Biochemistry (Moscow) 58, 424-437 (Engl. transl. 58, 325-337).

  21. Kholodenko, B.N. & Demin, O.V. (1993) Parametric stabilization and dynamic stability of the steady-states in metabolic pathways. What are the optimal structures? Biochemistry (Moscow) 58, 512-528 (Engl. transl. 58, 270-281).

  22. Demin, O.V. & Kholodenko, B.N. (1993) Structure of metabolic pathways that combine the high quality of end-product stabilization with high transition rates. Biochemistry (Moscow) 58, 997 -1008 (Engl.transl., 58, 692-701).

  23. Westerhoff, H.V., Hofmeyr, J.-H.S. & Kholodenko, B.N. (1994) Getting inside of cells using metabolic control analysis. Biophys. Chem. 50, 273-283.

  24. Kholodenko, B.N., Cascante, M. & Westerhoff, H.V. (1994) Control theory of metabolic channelling. In: Cellular bioenergetics: role of coupled creatine kinases. (Eds. V. Saks, R. Ventura-Clapier) Kluwer Academic Publishers, Dordrecht-Boston. p.312-332.

  25. Kholodenko, B.N., Cascante, M. & Westerhoff, H.V. (1994) Control theory of metabolic channelling. Mol. Cell. Biochem. 133/134, 313-331.

  26. Snoep, J.L., Jensen, P.R., Groeneveld, P., Molenaar, D., Kholodenko, B.N. & Westerhoff, H.V. (1994) How to determine control of growth rate in a chemostat. Using metabolic control analysis to resolve the paradox. Biochem. Mol. Biol. Intern. 33, 1023-1032.

  27. Kholodenko, B.N. & Westerhoff, H.V. (1994) Control theory of one enzyme. Biochim. Biophys. Acta. 1208, 294-305.

  28. Kholodenko, B.N., Sauro, H.M. & Westerhoff, H.V. (1994) Control by enzymes, coenzymes and conserved moieties: a generalization of the connectivity theorem of metabolic control analysis. Eur. J. Biochem. 225, 179-186.

  29. Kholodenko, B.N., Westerhoff, H.V. & Brown, G.C. (1994) Rate limitation within a single enzyme is directly related to enzyme intermediate levels. FEBS Lett. 349, 131-134.

  30. Kholodenko, B.N., Cascante, M. & Westerhoff, H.V. (1996) Control and regulation of channelled versus ideal pathways. In: Channelling and Intermediary Metabolism (Eds. L.Agius & H.S.A. Sherratt,) pp.91-114.

  31. Kholodenko, B.N., Schuster, S., Rohwer, J. M., Cascante, M. & Westerhoff, H.V. (1995) Composite control of cell function: metabolic pathways behaving as single control units. FEBS Lett. 368, 1-4.

  32. Kholodenko, B.N., Cascante, M., Molenaar, D., Demin, O.V., Gugten van der, A.A. & Westerhoff, H.V. (1995) Control theory of cell metabolism: towards more realistic "non-ideal" systems. J. Biol. Syst. 3, 145-154.

  33. Cascante, M., Melendez-Hevia, E., Kholodenko, B.N., Sicilia, J. & Kacser, H. (1995) Control analysis of transit time for free and enzyme-bound metabolites. Biochem. J. 308, 895-899.

  34. Mildaziene, V., Baniene, R., Nauciene, Z., Bakker, B. M., Westerhoff, H.V., Brown, G.C. & Kholodenko, B.N. (1995) Calcium indirectly increases the control exerted by the adenine nucleotide translocator over 2-oxoglutarate oxidation in rat heart mitochondria. Arch. Biochem. Biophys., 324, 130-134.

  35. Kholodenko, B.N., Westerhoff, H.V., Puigjaner, J. & Cascante, M. (1995) Control in channelled pathways. A matrix method calculating the enzyme control coefficients. Biophys. Chem. 53, 247-258.

  36. Kholodenko, B.N. & Westerhoff, H.V. (1995) The macro- versus microworld of biochemical regulation and control. Trends Biochem. Sci,. 20, 52-54.

  37. Kholodenko, B.N., Molenaar, D., Schuster, S., Heinrich, R. & Westerhoff, H.V. (1995) Defining control coefficients in "non-ideal" metabolic pathways. Biophys. Chem. 56, 215-226.

  38. Kholodenko, B.N. & Westerhoff, H.V. (1995) Control theory of group-transfer pathways. Biochim. Biophys. Acta, 1229, 256-274.

  39. Kholodenko, B.N. & Westerhoff, H.V. (1995) How to reveal various aspects of regulation in group-transfer pathways. Biochim. Biophys. Acta 1229, 275-289.

  40. Kholodenko, B.N., Sauro, H.M., Westerhoff, H.V. & Cascante, M. (1995) Coenzyme cycles and metabolic control analysis: the determination of the elasticity coefficients from the generalized connectivity theorem. Biochem. Mol. Biol. Intern. 35, 615-625.

  41. Jensen, P.R., Snoep, J.L., Molenaar, D., Van Heeswijk, W.C., Kholodenko, B.N., Van der Gugten, A.A. & Westerhoff, H.V. (1995) Molecular Biology for Flux Control Coefficients. Biochem. Soc. Trans. 23, 364-368.

  42. Westerhoff, H.V., Kholodenko, B.N., Cascante, M. & Van Dam, K. (1995) Elusive control. J. Bioenerg. Biomembr. 27, 491-497.

  43. Cascante, M., Puigjaner, J. & Kholodenko, B.N. (1996) Steady-state characterization of systems with moiety-conservations made easy. J.theor.Biol. 178, 1-6.

  44. Kholodenko, B.N., Westerhoff, H.V. & Cascante, M. (1996) Channelling and the concentration of bulk phase intermediates as cytosolic proteins get more concentrated. Biochem. J. 313, 921-926.

  45. Brown, G.C., Westerhoff, H.V. & Kholodenko, B.N. (1996). Molecular contol analysis: Control within proteins and molecular processes. J. theor. Biol. 182, 389-396.

  46. Kholodenko, B.N. & Brown G. (1996) Extension of Metabolic Control Analysis to physiology: control by body organs in vivo. In BioThermoKinetics of the Living Cell (Westerhoff H.V., Snoep J.L., Sluse F.E., Wijker J.E. & Kholodenko B.N., eds.), BioThermoKinetics, Amsterdam, pp. 163-167.

  47. Kholodenko, B.N. & Brown, G.C. (1996) Paradoxical properties of enzymes within pathways: can activation cause an enzyme to have increased control? Biochem. J. 314, 753-760.

  48. Kholodenko, B.N., Sakamoto, N., Puigjaner, J., Westerhoff, H.V. & Cascante, M. (1996) Strong control on the transit time in metabolic channelling. FEBS Lett. 389, 123-125.

  49. Bier M., Teusink B., Kholodenko B.N., & Westerhoff H.V. (1996) Control analysis of glycolytic oscillations. Biophys. Chem. 62,15-24.

  50. Mildaziene, V., Baniene, R., Nauciene, Z., Marcinkeviciute, A., Borutaite, V., Brown, G.C. & Kholodenko, B.N. (1996) Calcium stimulates both respiratory and phosphosylation subsystem in heart mitochondria. Biochem. J. 320, 329-334.

  51. Kholodenko, B. N., Demin, O. V. & Westerhoff, H. V. Control analysis of periodic phenomena in biological systems. (1997) J. Phys. Chem. 101, 2070-2081.

  52. Brown, G. C., Hoek, J.B. & Kholodenko, B. N. (1997) Why do protein kinase cascades have more than one level? Trends Biochem. Sci,. 22, 288.

  53. Kholodenko, B. N., Hoek, J. B., Westerhoff, H. W. & Brown, G. C. (1997) Quantification of information transfer via cellular signal transduction pathways. FEBS Lett. 414, 430-434.

  54. Kholodenko, B. N., Rower, J., Cascante, M. & Westerhoff, H. W. (1998) Subtleties in control by metabolic channelling and enzyme organization. Mol. Cell. Biochem. 184, 311-320.

  55. Kholodenko, B. N., Shuster, S., Garcia, J., Westerhoff, H. W. & Cascante, M. (1998) Control analysis of metabolic systems involving quasi-equilibrium reactions. Biochim. Biophys. Acta, 1379, 337-352.

  56. Westerhoff, H.V., Jensen, P.R., Snoep, J.L. & Kholodenko, B.N. (1998) Thermodynamics of complexity. The live cell. Thermochim. Acta, 309, 111-120.

  57. Kholodenko, B. N., Cascante, M., Hoek, J. B., Westerhoff, H. W. & Schwaber, J. (1998) Metabolic design: how to engineer a living cell to desired metabolite concentrations and fluxes. Biotechnol. Bioeng. 59, 239-247.

  58. Demin, O.V., Kholodenko, B.N. & Skulachev, V.P. (1998) A model of superoxide generation in the complex III of the electron transport chain. Mol. Cell. Biochem. 184, 21-33.

  59. Hoek, J. B. & Kholodenko, B. N. (1998) The intracellular signaling network as a target for ethanol. Alcohol. Clin. Exp. Res. 22, 224S-230S.

  60. Rower, J., Postma, P., Kholodenko, B.N. & Westerhoff, H. W. (1998) Implications of macromolecular crowding for signal transduction and metabolic channeling. Proc. Natl. Acad. Sci 95, 10547-10552.

  61. Brown, G. C. & Kholodenko, B. N. Spatial gradients of cellular phospho-proteins. (1999) FEBS Lett, 457, 452-454.

  62. Kholodenko, B.N., Demin, O.V., Moehren, G. & Hoek, J.B. (1999) Quantification of short-term signaling by the epidermal growth factor receptor. JBC, 274, 30169-30181.

  63. Demin, O.V., Westerhoff, H. W. & Kholodenko, B.N. (1999) Control analysis of stationary forced oscillations. J. Phys. Chem. B 103, 10695-10710.

  64. Kholodenko, B.N. (2000) Negative feedback and ultrasensitivity can bring about oscillations in the mitogen activated protein kinase cascades. Eur. J. Biochem. 267: 1583-1588.

  65. Schuster, S., B. N. Kholodenko & H. V. Westerhoff. (2000) Cellular information transfer regarded from a stoichiometry and control analysis perspective. Biosystems 55: 73-81.

  66. Kholodenko, B. N., Westerhoff, H. W., Schwaber, J. & Cascante, M. (2000) Engineering a living cell to desired metabolite concentrations and fluxes: pathways with multifunctional enzymes. Metabolic Engineer. 2, 1-13.

  67. Kholodenko, B.N., Hoek, J.B. & Westerhoff, H.V. (2000) Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends Cell Biol. 10, 173-178.

  68. Marcinkeviciute A., Mildaziene V., Crumm S., Demin O., Hoek, J.B. & Kholodenko, B. (2000) Kinetics and control of oxidative phosphorylation in rat liver mitochondria after chronic ethanol feeding. Biochem. J. 349, 519-526.

  69. Kholodenko, B. N., G. C. Brown & Hoek, J.B. (2000). Diffusion control of protein phosphorylation in signal transduction pathways. Biochem. J. 350, 901-907.

  70. Markevich, N., Kiyatkin, A. B., Zak D. E., Pastorino, J. G., Hoek, J. B. & Kholodenko, B. N. (2001) Four-Dimensional Organization Of Cellular Signal Transduction Cascades. Proceedings of the Second International Conference on System Biology. 141-147. Pasadena, CA, USA.

  71. De Atauri, P., Acerenza, L, Kholodenko, B. N., De La Iglesia N, Guinovart, JJ, Agius L, & Cascante, M. (2001) Occurrence of paradoxical or sustained control by an enzyme when overexpressed: necessary conditions and experimental evidence with regard to hepatic glucokinase. Biochem. J. 355, 787-793.

  72. Moehren, G., Markevich, N., Demin, O.V. Kiyatkin, A., Hoek, J.B. & Kholodenko, B.N. (2002) Temperature dependence of epidermal growth factor receptor signaling can be accounted for by a kinetic model. Biochemistry 41, 306-320.

  73. Reijenga K.A., Westerhoff H.V., Kholodenko B. N.& Snoep J. L. (2002) Control Analysis for Autonomously Oscillating Biochemical Networks. Biophys. J. 82, 99-108.

  74. Kholodenko, B.N. (2002) Map kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends Cell Biol. 12, 173-177.

  75. Bruggeman, F. J. & Kholodenko, B. N. (2002) Modular interaction strengths in regulatory networks; an example. Mol Biol. Rep. 29, 57-61.

  76. Kholodenko B.N, Kiyatkin A, Bruggeman, F., Sontag, E, Westerhoff, H.V. & Hoek, JB. (2002) Untangling the wires: A strategy to trace functional interactions in signaling and gene networks. Proc. Natl. Acad. Sci., USA, 20, 12841-12846.

  77. Bruggeman, F.J., Westerhoff, H.V., Hoek, J. B. & Kholodenko, B. N. (2002) Modular Response Analysis of Cellular Regulatory Networks. J. theor. Biol. 218, 507-520.

  78. Kholodenko, B. N. (2003) Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors. J. Exp. Biol., 206, 2073-2082.

  79. Peletier, M.A., Westerhoff, H. W. & Kholodenko, B. N. (2003) Control of Spatially Heterogeneous Cellular Reaction Networks. A New Summation Law. J. theor. Biol. 225, 477-487.

  80. Westerhoff H.V. & Kholodenko B.N. (2003) Metabolic Engineering, What it was and What it is. In: Metabolic Engineering in the Post Genomic Era, pp. 1-35 (Eds. Kholodenko B.N. & Westerhoff H.V.) Horizon Bioscience, Norfolk, England.

  81. Westerhoff H.V. & Kholodenko B.N. (2003) Metabolic engineering in the postgenomic era: what it should become. In: Metabolic Engineering in the Post Genomic Era, pp. 435-442, (Eds. Kholodenko B.N. & Westerhoff H.V.) Horizon Bioscience, Norfolk, England.

  82. Suenaga, A., Kiyatkin, A. B., Hatakeyama, M., Futatsugi, N., Okimoto, N., Hirano, Y., Narumi, T., Kawai, A., Susukita, R., Koishi, T., Furusawa, H., Yasuoka, K., Takada, N., Ohno, Y., Taiji, M., Ebisuzaki, T., Hoek, J. B., Konagaya, A. & Kholodenko, B. N. (2004). Tyr317 phosphorylation increases Shc structural rigidity and reduces coupling of domain motions remote from the phosphorylation site as revealed by molecular dynamics simulations. J Biol. Chem. 279, 4657-4662.

  83. Markevich, N., Hoek, J. B. & Kholodenko, B. N. (2004). Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J Cell Biology, 164, 353-359.

  84. Sontag, E., Kiyatkin, A. & Kholodenko, B. N. (2004). Inferring Dynamic Architecture of Cellular Networks Using Time Series of Gene Expression, Protein and Metabolite Data. Bioinformatics, 20, 1877-1886.

  85. Sauro, H.M & Kholodenko, B.N. (2004) Quantitative analysis of signaling networks. Prog Biophys Mol Biol. 86(1), 5-43.

  86. Markevich, N. I., Moehren, G., Demin, O., Kiyatkin, A., Hoek, J. B. & Kholodenko, B. N. (2004) Signal processing at the Ras circuit: What shapes Ras activation patterns? IEE Systems Biology 1, 104-113.

  87. Andrec, M., Kholodenko, B.N., Levy, R.M. & Sontag E. (2005) Inference of signaling and gene regulatory networks by steady-state perturbation experiments: structure and accuracy. J. Theor. Biol. 232, 427-441.

  88. Borisov N.M., Markevich, N.I., Hoek J.B. & Kholodenko B.N. (2005) Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity. Biophys J. 89, 951-966.

  89. Bluthgen, N., Bruggeman, F. J., Legewie, S., Herzel, H., Westerhoff, H. V. & Kholodenko, B. N. (2006) Effects of sequestration on signal transduction cascades. Febs J. 273, 895-906.

  90. Borisov, N. M., Markevich, N. I., Hoek, J. B. & Kholodenko, B. N. (2006) Trading the micro-world of combinatorial complexity for the macro-world of protein interaction domains. Biosystems. 83, 152-66.

  91. Conzelmann, H., Saez-Rodriguez, J., Sauter, T., Kholodenko, B. N. & Gilles, E. D. (2006) A domain-oriented approach to the reduction of combinatorial complexity in signal transduction networks. BMC Bioinformatics. 7, 34 doi:10.1186/1471-2105-7-34.

  92. Kholodenko, B. N. (2006) Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol. Epub ahead of print, PMID: 16482094