scholarly journals Metabolic Control Analysis of glycolysis in tuber tissue of potato (Solanum tuberosum): explanation for the low control coefficient of phosphofructokinase over respiratory flux

1997 ◽  
Vol 322 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Simon THOMAS ◽  
Peter J. F. MOONEY ◽  
Michael M. BURRELL ◽  
David A. FELL
Keyword(s):  
Potato Tuber ◽  
Metabolic Control ◽  
Kinetic Data ◽  
Metabolic Control Analysis ◽  
Glycolytic Flux ◽  
Control Analysis ◽  
Tuber Tissue ◽  
Flux Control ◽  
Calculated Concentration ◽  
Control Coefficients

We have applied Metabolic Control Analysis (MCA) in an attempt to determine the distribution of glycolytic flux control between the steps of glycolysis in aged disks of potato tuber under aerobic conditions, using concentrations of glycolytic metabolites in tuber tissue from a range of transgenic potato plants and published enzyme kinetic data. We modelled the substrate and effector kinetics of potato tuber phosphofructokinase (PFK) by reanalysing published results. Despite the scarcity of reliable kinetic data, our results are in agreement with experimental findings namely that, under the conditions described, PFK has little control over glycolytic flux. Furthermore our analysis predicts that under these conditions far more control lies in the dephosphorylation of phosphoenolpyruvate and/or in the steps beyond. We have validated the results of our analysis in two ways. First, predictions based on calculated concentration control coefficients from the analysis show generally good agreement with observed metabolite deviation indices discussed in the preceding paper [Thomas, Mooney, Burrell, and Fell (1997) Biochem. J.322, 111Ő117]. Second, sensitivity analysis of our results shows that the calculated control coefficients are robust to errors in the elasticities used in the analysis, of which relatively few need to be known accurately. Experimental and control analysis results agree with previous predictions of MCA that strong co-operative feedback inhibition of enzymes serves to move flux control downstream of the inhibiting metabolite. We conclude that MCA can successfully model the outcome of experiments in the genetic manipulation of enzyme amounts.

scholarly journals Metabolic control analysis of biochemical pathways based on a thermokinetic description of reaction rates

1997 ◽  
Vol 321 (1) ◽  
pp. 133-138 ◽  
Author(s):  
Jens NIELSEN
Keyword(s):  
Metabolic Control ◽  
Reaction Rate ◽  
Reaction Rates ◽  
Rate Function ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Flux Control ◽  
Biochemical Pathways ◽  
Flux Control Coefficients

Metabolic control analysis is a powerful technique for the evaluation of flux control within biochemical pathways. Its foundation is the elasticity coefficients and the flux control coefficients (FCCs). On the basis of a thermokinetic description of reaction rates it is here shown that the elasticity coefficients can be calculated directly from the pool levels of metabolites at steady state. The only requirement is that one thermodynamic parameter be known, namely the reaction affinity at the intercept of the tangent in the inflection point of the curve of reaction rate against reaction affinity. This parameter can often be determined from experiments in vitro. The methodology is applicable only to the analysis of simple two-step pathways, but in many cases larger pathways can be lumped into two overall conversions. In cases where this cannot be done it is necessary to apply an extension of the thermokinetic description of reaction rates to include the influence of effectors. Here the reaction rate is written as a linear function of the logarithm of the metabolite concentrations. With this type of rate function it is shown that the approach of Delgado and Liao [Biochem. J. (1992) 282, 919–927] can be much more widely applied, although it was originally based on linearized kinetics. The methodology of determining elasticity coefficients directly from pool levels is illustrated with an analysis of the first two steps of the biosynthetic pathway of penicillin. The results compare well with previous findings based on a kinetic analysis.

scholarly journals A computer program for the algebraic determination of control coefficients in Metabolic Control Analysis

1993 ◽  
Vol 292 (2) ◽  
pp. 351-360 ◽  
Author(s):  
S Thomas ◽  
D A Fell
Keyword(s):  
Computer Program ◽  
Metabolic Control ◽  
Matrix Method ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Point Distribution ◽  
Algebraic Expressions ◽  
The Matrix ◽  
Control Coefficients

A computer program (MetaCon) is described for the evaluation of flux control, concentration control and branch-point distribution control coefficients of a metabolic pathway. Requiring only the reaction scheme as input, the program produces algebraic expressions for the control coefficients in terms of elasticity coefficients, metabolite concentrations and pathway fluxes. Any of these variables can be substituted by numeric or simple algebraic expressions; the expressions will then be automatically rearranged in terms of the remaining unknown variables. When all variables have been substituted, numeric values will be obtained for the control coefficients. The program is a computerized implementation of the matrix method for the determination of control coefficients. The features of MetaCon are compared with those of other programs available to workers in Metabolic Control Analysis. Potential benefits of, and methods of using, MetaCon are discussed. The mathematical background and validity of the matrix method rules are discussed, and the algorithm used by MetaCon is described. The matrix method is shown to be a specific case of a previously described general formalism for calculating control coefficients.

scholarly journals Metabolic control analysis of anaerobic glycolysis in human hibernating myocardium replaces traditional concepts of flux control

FEBS Letters ◽  
2002 ◽  
Vol 517 (1-3) ◽  
pp. 245-250 ◽  
Author(s):  
Achim M. Vogt ◽  
Holger Nef ◽  
Jutta Schaper ◽  
Mark Poolman ◽  
David A. Fell ◽  
...  
Keyword(s):  
Metabolic Control ◽  
Metabolic Control Analysis ◽  
Hibernating Myocardium ◽  
Control Analysis ◽  
Anaerobic Glycolysis ◽  
Flux Control

scholarly journals Metabolic Control Analysis of Exponential Growth and Product Formation

2018 ◽  
Author(s):  
David Andrew Fell
Keyword(s):  
Steady State ◽  
Metabolic Control ◽  
Product Yield ◽  
Product Formation ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Control Coefficient ◽  
Flux Control ◽  
Flux Control Coefficient ◽  
Metabolic Fluxes

Metabolic Control Analysis defines the relationships between the change in activity of an enzyme and the resulting impacts on metabolic fluxes and metabolite concentrations at steady state. In many biotechnological applications of metabolic engineering, however, the goal is to alter the product yield. In this case, although metabolism may be at a pseudo-steady state, the amount of biomass catalysing the metabolism can be growing exponentially. Here, expressions are derived that relate the change in activity of an enzyme and its flux control coefficient to the change in yield from an exponentially growing system. Conversely, the expressions allow estimation of an enzyme's flux control coefficient over the pathway generating the product from measurements of the changes in enzyme activity and yield.

Use of metabolic control analysis in lactation biology

2008 ◽  
Vol 146 (3) ◽  
pp. 267-273 ◽  
Author(s):  
T. C. WRIGHT ◽  
J. P. CANT ◽  
B. W. MCBRIDE
Keyword(s):  
Sensitivity Analysis ◽  
Fatty Acid ◽  
Metabolic Control ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Acetyl Coa Carboxylase ◽  
Rate Limiting ◽  
Control Coefficients

SUMMARYSensitivity analysis is routinely carried out in the evaluation of simulation models to identify the degree to which parameters influence model outputs. This type of sensitivity analysis is much less frequently applied to real systems, but a technique called metabolic control analysis (MCA) was developed in the 1970s for the purpose of experimentally identifying the degree to which individual enzymes in a metabolic pathway influence flux through the pathway. MCA is applied to the results of inhibition, activation or genetic manipulation of enzymatic steps in a biochemical pathway. Flux control coefficients for each enzyme are defined as the fractional change in steady-state flux through the entire pathway for an infinitesimal change in the activity of that one enzyme. The sum of control coefficients in a linear, non-branching pathway is equal to one. It is a common finding in MCA that the control, or sensitivity, is distributed over multiple enzymes and not in a single rate-limiting enzyme. The fundamental principles of MCA are reviewed and an overview of experimental methods to measure control coefficients is provided, with the objective of introducing this approach to the fields of agricultural biochemistry and modelling, where it is little known. The application of MCA to the study of glucose metabolism and fatty acid synthesis in bovine mammary tissue are reviewed. The analyses indicated that mammary hexokinase activity exerts more control than transmembrane transport of glucose over lactose synthesis, and that control of cytosolic fatty acid synthesis is shared between acetyl-CoA carboxylase and fatty acid synthase, contrary to the widely held view that acetyl CoA carboxylase is the rate-limiting enzyme. It is suggested that MCA could be a valuable aid in the integration of proteomic and metabolomic data with metabolic flux measurements to engineer desired changes in the composition of milk from dairy animals.

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