Dynamic sensitivity analysis for metabolic systems

This paper illustrates a new method for the determination of steady-state and time-dependent control coefficients to be obtained from dynamic metabolic models. This method is based on the rapidly advancing techniques for monitoring and modelling intracellular pool changes following extracellular system perturbation. In addition to the attraction of computing steady-state and dynamic flux control coefficients and concentration control coefficients, the importance of investigating both control exercised by enzyme amount and kinetic enzyme properties is highlighted. The application of this new method is illustrated with the aid of a simple metabolic model. Further, it is shown that control of intracellular dynamics can also be suitably affected through careful selection of dynamic extracellular system stimulation. The proposed method reveals the hierarchic structure of effective system manipulation and thus constitutes a valuable source of information for the optimization of metabolic engineering applications.

[1]  W. V. Loscutoff,et al.  General sensitivity theory , 1972 .

[2]  H. Kacser,et al.  Responses of metabolic systems to large changes in enzyme activities and effectors. 2. The linear treatment of branched pathways and metabolite concentrations. Assessment of the general non-linear case. , 1993, European journal of biochemistry.

[3]  J. Bailey,et al.  Toward a science of metabolic engineering , 1991, Science.

[4]  H. Kacser,et al.  Metabolic control analysis of moiety-conserved cycles. , 1986, European journal of biochemistry.

[5]  M. Kohn,et al.  Sensitivity to values of the rate constants in a neurochemical metabolic model. , 1983, Journal of theoretical biology.

[6]  Reinhart Heinrich,et al.  Mathematical analysis of multienzyme systems. II. Steady state and transient control. , 1975, Bio Systems.

[7]  J. Liao,et al.  Metabolic control analysis using transient metabolite concentrations. Determination of metabolite concentration control coefficients. , 1992, The Biochemical journal.

[8]  J. S. Easterby,et al.  Integration of temporal analysis and control analysis of metabolic systems. , 1990, The Biochemical journal.

[9]  R. V. Prasad,et al.  A strategy for increasing an in vivo flux by genetic manipulations. The tryptophan system of yeast. , 1992, The Biochemical journal.

[10]  M. Reuss,et al.  In vivo analysis of metabolic dynamics in Saccharomyces cerevisiae: II. Mathematical model. , 1997, Biotechnology and bioengineering.

[11]  M. Kohn,et al.  Metabolic network sensitivity analysis. , 1982, Journal of theoretical biology.

[12]  G. Brown,et al.  A 'top-down' approach to the determination of control coefficients in metabolic control theory. , 1990, European journal of biochemistry.

[13]  D. Fell.  Metabolic control analysis: a survey of its theoretical and experimental development. , 1992, The Biochemical journal.

[14]  J. Liao,et al.  Determination of Flux Control Coefficients from transient metabolite concentrations. , 1992, The Biochemical journal.

[15]  H. Sauro,et al.  Control analysis of time-dependent metabolic systems. , 1989, Journal of theoretical biology.

[16]  M. Reuss,et al.  In vivo analysis of glucose-induced fast changes in yeast adenine nucleotide pool applying a rapid sampling technique. , 1993, Analytical biochemistry.

[17]  D. Fell,et al.  Metabolic control and its analysis , 1985 .

[18]  Reinhart Heinrich,et al.  A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. , 1974, European journal of biochemistry.

[19]  H. Kacser,et al.  The control of flux. , 1995, Biochemical Society transactions.

[20]  A J Sinskey,et al.  Metabolic engineering--methodologies and future prospects. , 1993, Trends in biotechnology.

[21]  C Reder,et al.  Metabolic control theory: a structural approach. , 1988, Journal of theoretical biology.

[22]  B. Kholodenko,et al.  The macroworld versus the microworld of biochemical regulation and control. , 1995, Trends in biochemical sciences.

[23]  M. Kohn,et al.  Instantaneous flux control analysis for biochemical systems. , 1979, Journal of theoretical biology.

[24]  H V Westerhoff,et al.  Getting to the inside of cells using metabolic control analysis. , 1994, Biophysical chemistry.

[25]  R Heinrich,et al.  Metabolic regulation and mathematical models. , 1977, Progress in biophysics and molecular biology.

[26]  N V Torres,et al.  Analysis and characterization of transition states in metabolic systems. Transition times and the passivity of the output flux. , 1991, The Biochemical journal.

[27]  A. Cornish-Bowden.  Metabolic Control Analysis in Theory and Practice , 1995 .

[28]  Lennart Ljung,et al.  System Identification: Theory for the User , 1987 .

[29]  M. Reuss,et al.  In vivo analysis of metabolic dynamics in Saccharomyces cerevisiae : I. Experimental observations. , 1997, Biotechnology and bioengineering.

[30]  R. Heinrich,et al.  Metabolic control analysis of relaxation processes , 1991 .

[31]  J R Small.  Flux control coefficients determined by inhibitor titration: the design and analysis of experiments to minimize errors. , 1993, The Biochemical journal.

[32]  H. Kacser,et al.  Kinetics of metabolic pathways. A system in vitro to study the control of flux. , 1986, The Biochemical journal.

[33]  H. Westerhoff,et al.  How do enzyme activities control metabolite concentrations? An additional theorem in the theory of metabolic control. , 1984, European journal of biochemistry.

[34]  A. Cornish-Bowden,et al.  Control analysis of metabolic systems , 1985 .

[35]  G Zacchi,et al.  Influence of experimental errors on the determination of flux control coefficients from transient metabolite concentrations. , 1996, The Biochemical journal.