Regulation and Control in Complex, Dynamic Metabolic Systems: Experimental Application of the Top-Down Approaches of Metabolic Control Analysis to Fatty Acid Oxidation and Ketogenesis

1996 ◽  
Vol 182 (3) ◽  
pp. 381-388 ◽  
Author(s):  
Stefan Krauss ◽  
Patti A. Quant
Keyword(s):  
Fatty Acid ◽  
Metabolic Control ◽  
Metabolic Control Analysis ◽  
Acid Oxidation ◽  
Control Analysis ◽  
Top Down ◽  
Complex Dynamic ◽  
Experimental Application ◽  
Metabolic Systems ◽  
And Control

Regulation analysis of energy metabolism.

1997 ◽  
Vol 200 (2) ◽  
pp. 193-202 ◽  
Author(s):  
M D Brand
Keyword(s):  
Steady State ◽  
Energy Metabolism ◽  
Metabolic Control Analysis ◽  
Steady States ◽  
Control Analysis ◽  
Top Down ◽  
Down Regulation ◽  
Metabolic Systems ◽  
And Control ◽  
Control Coefficients

This paper reviews top-down regulation analysis, a part of metabolic control analysis, and shows how it can be used to analyse steady states, regulation and homeostasis in complex systems such as energy metabolism in mitochondria, cells and tissues. A steady state is maintained by the variables in a system; regulation is the way the steady state is changed by external effectors. We can exploit the properties of the steady state to measure the kinetic responses (elasticities) of reactions to the concentrations of intermediates and effectors. We can reduce the complexity of the system under investigation by grouping reactions into large blocks connected by a small number of explicit intermediates-this is the top-down approach to control analysis. Simple titrations then yield all the values of elasticities and control coefficients within the system. We can use these values to quantify the relative strengths of different internal pathways that act to keep an intermediate or a rate constant in the steady state. We can also use them to quantify the relative strengths of different primary actions of an external effector and the different internal pathways that transmit its effects through the system, to describe regulation and homeostasis. This top-down regulation analysis has been used to analyse steady states of energy metabolism in mitochondria, cells and tissues, and to analyse regulation of energy metabolism by cadmium, an external effector, in mitochondria. The combination of relatively simple experiments and new theoretical structures for presenting and interpreting the results means that top-down regulation analysis provides a novel and effective way to analyse steady states, regulation and homeostasis in intricate metabolic systems.

scholarly journals Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations1: computer simulation and Metabolic Control Analysis

1999 ◽  
Vol 342 (3) ◽  
pp. 597-604 ◽  
Author(s):  
Peter J. MULQUINEY ◽  
Philip W. KUCHEL
Keyword(s):  
Computer Simulation ◽  
Metabolic Control ◽  
Energy Demand ◽  
Feedback Inhibition ◽  
Oxygen Affinity ◽  
Metabolic Control Analysis ◽  
Product Inhibition ◽  
Control Analysis ◽  
And Control

This is the third of three papers [see also Mulquiney, Bubb and Kuchel (1999) Biochem. J. 342, 565-578; Mulquiney and Kuchel (1999) Biochem. J. 342, 579-594] for which the general goal was to explain the regulation and control of 2,3-bisphosphoglycerate (2,3-BPG) metabolism in human erythrocytes. 2,3-BPG is a major modulator of haemoglobin oxygen affinity and hence is vital in blood oxygen transport. A detailed mathematical model of erythrocyte metabolism was presented in the first two papers. The model was refined through an iterative loop of experiment and simulation and it was used to predict outcomes that are consistent with the metabolic behaviour of the erythrocyte under a wide variety of experimental and physiological conditions. For the present paper, the model was examined using computer simulation and Metabolic Control Analysis. The analysis yielded several new insights into the regulation and control of 2,3-BPG metabolism. Specifically it was found that: (1) the feedback inhibition of hexokinase and phosphofructokinase by 2,3-BPG are equally as important as the product inhibition of 2,3-BPG synthase in controlling the normal in vivo steady-state concentration of 2,3-BPG; (2) H+ and oxygen are effective regulators of 2,3-BPG concentration and that increases in 2,3-BPG concentrations are achieved with only small changes in glycolytic rate; (3) these two effectors exert most of their influence through hexokinase and phosphofructokinase; (4) flux through the 2,3-BPG shunt changes in absolute terms in response to different energy demands placed on the cell. This response of the 2,3-BPG shunt contributes an [ATP]-stabilizing effect. A ‘cost’ of this is that 2,3-BPG concentrations are very sensitive to the energy demand of the cell and; (5) the flux through the 2,3-BPG shunt does not change in response to different non-glycolytic demands for NADH.

CONTROL ANALYSIS OF METABOLIC SYSTEMS CONSISTING OF UNI- AND/OR MULTIFUNCTIONAL UNITS: APPLICATION TO MODULAR SYSTEMS AND SLIPPING ENZYMES

1995 ◽  
Vol 03 (01) ◽  
pp. 217-230 ◽  
Author(s):  
STEFAN SCHUSTER ◽  
DANIEL KAHN ◽  
HANS V. WESTERHOFF
Keyword(s):  
Metabolic Control ◽  
Quantitative Method ◽  
Control Structure ◽  
Metabolic Control Analysis ◽  
Reaction Networks ◽  
Control Analysis ◽  
Modular Systems ◽  
Metabolic Systems ◽  
Mutual Regulation ◽  
Flux Response

We present a quantitative method based on Metabolic Control Analysis that makes possible to subdivide large metabolic systems into modules and to integrate the information concerning the flux response of these modules so as to yield understanding of the control structure in terms of the mutual regulation of the modules. This work generalizes previous analyses of overall control properties in that it considers multiple fluxes to connect the modules and reaction networks of any complexity. The approach is applied to slipping enzymes.

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