scholarly journals Metabolic Control Analysis: A Tool for Designing Strategies to Manipulate Metabolic Pathways

2008 ◽  
Vol 2008 ◽  
pp. 1-30 ◽  
Author(s):  
Rafael Moreno-Sánchez ◽  
Emma Saavedra ◽  
Sara Rodríguez-Enríquez ◽  
Viridiana Olín-Sandoval
Keyword(s):  
Metabolic Control ◽  
Metabolic Pathway ◽  
Large Scale ◽  
Metabolic Control Analysis ◽  
Metabolite Concentration ◽  
Control Analysis ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Experimental Approaches ◽  
Rate Limiting

The traditional experimental approaches used for changing the flux or the concentration of a particular metabolite of a metabolic pathway have been mostly based on the inhibition or over-expression of the presumed rate-limiting step. However, the attempts to manipulate a metabolic pathway by following such approach have proved to be unsuccessful. Metabolic Control Analysis (MCA) establishes how to determine, quantitatively, the degree of control that a given enzyme exerts on flux and on the concentration of metabolites, thus substituting the intuitive, qualitative concept of rate limiting step. Moreover, MCA helps to understand (i) the underlying mechanisms by which a given enzyme exerts high or low control and (ii) why the control of the pathway is shared by several pathway enzymes and transporters. By applying MCA it is possible to identify the steps that should be modified to achieve a successful alteration of flux or metabolite concentration in pathways of biotechnological (e.g., large scale metabolite production) or clinical relevance (e.g., drug therapy). The different MCA experimental approaches developed for the determination of the flux-control distribution in several pathways are described. Full understanding of the pathway properties when working under a variety of conditions can help to attain a successful manipulation of flux and metabolite concentration.

Two (completely) rate-limiting steps in one metabolic pathway? The resolution of a paradox using bacteriorhodopsin liposomes and the control theory

1984 ◽  
Vol 4 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Hans V. Westerhoff ◽  
Jos C. Arents
Keyword(s):  
Membrane Potential ◽  
Control Theory ◽  
Metabolic Pathway ◽  
Proton Pumping ◽  
Control Coefficient ◽  
Rate Limiting Step ◽  
Ion Movement ◽  
Limiting Step ◽  
Proton Uptake ◽  
Rate Limiting

Proton pumping by bacteriorhodopsin and chargecompensating ion movement can both and simultaneously behave as the rate-limiting step in light-driven proton uptake into bacteriorhodopsin liposomes. This apparently excessive control exerted on the net proton influx is possible because of the negative (−1) ‘control coefficient” of the net proton influx with respect to the proton leaks. Furthermore, the property of bacteriorhodopsin that it is inhibited by the membrane potential is responsible for the transfer of part of the control on the net proton influx from the first, irreversible, step in the pathway (i.e. bacteriorhodopsin) to the second, reversible, step (i.e., charge-compensating ion movement).

scholarly journals Control analysis applied to single enzymes: can an isolated enzyme have a unique rate-limiting step?

1993 ◽  
Vol 294 (1) ◽  
pp. 87-94 ◽  
Author(s):  
G C Brown ◽  
C E Cooper
Keyword(s):  
Rate Constants ◽  
General Assumption ◽  
Control Analysis ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Steady State Rate ◽  
Carbamate Kinase ◽  
State Rate ◽  
Rate Limiting ◽  
Control Coefficients

Control analysis is used to analyse and quantify the concept of a rate-limiting step within an enzyme. The extent to which each rate constant within the enzyme limits the steady-state rate of the enzyme and the levels of enzyme intermediate species are quantified as flux and concentration control coefficients. These coefficients are additive and obey summation theorems. The control coefficients of triose phosphate isomerase, carbamate kinase and lactate dehydrogenase are calculated from literature values of the rate constants. It is shown that, contrary to previous assumption, these enzymes do not have a unique rate-limiting step, but rather flux control is shared by several rate constants and varies with substrate, product and effector concentrations, and with the direction of the reaction. Thus the general assumption that an enzyme will have a unique rate-limiting step is unjustified.

scholarly journals Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Alexander A Shestov ◽  
Xiaojing Liu ◽  
Zheng Ser ◽  
Ahmad A Cluntun ◽  
Yin P Hung ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Metabolic Control Analysis ◽  
Integrated Analysis ◽  
Control Analysis ◽  
Metabolomics Data ◽  
Limiting Step ◽  
Quantitative Changes ◽  
Fructose 1,6 Bisphosphate ◽  
And Control ◽  
Rate Limiting

Aerobic glycolysis or the Warburg Effect (WE) is characterized by the increased metabolism of glucose to lactate. It remains unknown what quantitative changes to the activity of metabolism are necessary and sufficient for this phenotype. We developed a computational model of glycolysis and an integrated analysis using metabolic control analysis (MCA), metabolomics data, and statistical simulations. We identified and confirmed a novel mode of regulation specific to aerobic glycolysis where flux through GAPDH, the enzyme separating lower and upper glycolysis, is the rate-limiting step in the pathway and the levels of fructose (1,6) bisphosphate (FBP), are predictive of the rate and control points in glycolysis. Strikingly, negative flux control was found and confirmed for several steps thought to be rate-limiting in glycolysis. Together, these findings enumerate the biochemical determinants of the WE and suggest strategies for identifying the contexts in which agents that target glycolysis might be most effective.

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.

Ornithine Decarboxylase Activity in Cultured Endothelial Cells Stimulated by Serum, Thrombin and Serotonin

1978 ◽  
Vol 39 (02) ◽  
pp. 496-503 ◽  
Author(s):  
P A D’Amore ◽  
H B Hechtman ◽  
D Shepro
Keyword(s):  
Endothelial Cells ◽  
Ornithine Decarboxylase ◽  
Decarboxylase Activity ◽  
Aortic Endothelial Cells ◽  
Ornithine Decarboxylase Activity ◽  
Rate Limiting Step ◽  
Bovine Aortic Endothelial Cells ◽  
Limiting Step ◽  
Rate Limiting ◽  
Serum Serotonin

SummaryOrnithine decarboxylase (ODC) activity, the rate-limiting step in the synthesis of polyamines, can be demonstrated in cultured, bovine, aortic endothelial cells (EC). Serum, serotonin and thrombin produce a rise in ODC activity. The serotonin-induced ODC activity is significantly blocked by imipramine (10-5 M) or Lilly 11 0140 (10-6M). Preincubation of EC with these blockers together almost completely depresses the 5-HT-stimulated ODC activity. These observations suggest a manner by which platelets may maintain EC structural and metabolic soundness.

Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Diabetes ◽  
1993 ◽  
Vol 42 (2) ◽  
pp. 296-306 ◽  
Author(s):  
D. C. Bradley ◽  
R. A. Poulin ◽  
R. N. Bergman
Keyword(s):  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting
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