scholarly journals Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases

2000 ◽  
Vol 347 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Rodrigue ROSSIGNOL ◽  
Thierry LETELLIER ◽  
Monique MALGAT ◽  
Christophe ROCHER ◽  
Jean-Pierre MAZAT
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Diseases ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Control Coefficient ◽  
Experimental Conditions ◽  
Mitochondrial Cytopathies ◽  
Coefficient Distribution ◽  
Control Coefficients ◽  
Different Tissues

Metabolic control analysis has often been used for quantitative studies of the regulation of mitochondrial oxidative phosphorylations (OXPHOS). The main contribution of this work has been to show that the control of mitochondrial metabolic fluxes can be shared among several steps of the oxidative phosphorylation process, and that this distribution can vary according to the steady state and the tissue. However, these studies do not show whether this observed variation in the OXPHOS control is due to the experimental conditions or to the nature of the mitochondria. To find out if there actually exists a tissue variation in the distribution of OXPHOS control coefficients, we determined the control coefficients of seven OXPHOS complexes on the oxygen-consumption flux in rat mitochondria isolated from five different tissues under identical experimental conditions. Thus in this work, only the nature of the mitochondria can be responsible for any variation detected in the control coefficient values between different tissues. The analysis of control coefficient distribution shows two tissue groups: (i) the muscle and the heart, controlled essentially at the level of the respiratory chain; and (ii) the liver, the kidney and the brain, controlled mainly at the phosphorylation level by ATP synthase and the phosphate carrier. We propose that this variation in control coefficient according to the tissue origin of the mitochondria can explain part of the tissue specificity observed in mitochondrial cytopathies.

scholarly journals Integration of temporal analysis and control analysis of metabolic systems

1990 ◽  
Vol 269 (1) ◽  
pp. 255-259 ◽  
Author(s):  
J S Easterby
Keyword(s):  
Steady State ◽  
Transient Response ◽  
Temporal Analysis ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Control Coefficient ◽  
Temporal Control ◽  
Transient Time ◽  
Metabolic Systems ◽  
Control Coefficients

A theory is developed that integrates approaches to the analysis of pathway transient response and metabolic control analysis. A Temporal Control Coefficient is defined that is a measure of the system's transient response to modulation of enzyme activity or concentration. The approach allows for the analysis of the establishment of a steady state from rest, of the system's ‘agility’ of response to minor perturbations of a pre-existing steady state and of the macroscopic transition between steady states. In the last-mentioned case it is shown that, like the transient time itself, the control of transient response retains the property of independence from the mechanism of the transition. In consequence, the Temporal Control Coefficient can be defined in terms of the control properties of the initial and final states alone without reference to the mechanism of transition. A summation property is shown to apply to the Temporal Control Coefficients in each case. Connectivity relationships between elasticities and Temporal Control Coefficients are also established.

scholarly journals Metabolic control analysis using transient metabolite concentrations. Determination of metabolite concentration control coefficients

1992 ◽  
Vol 285 (3) ◽  
pp. 965-972 ◽  
Author(s):  
J Delgado ◽  
J C Liao
Keyword(s):  
Theoretical Basis ◽  
Metabolic Control Analysis ◽  
Metabolite Concentration ◽  
Quasi Equilibrium ◽  
Control Analysis ◽  
Algebraic Equations ◽  
Metabolite Concentrations ◽  
Flux Control Coefficients ◽  
Control Coefficients

The methodology previously developed for determining the Flux Control Coefficients [Delgado & Liao (1992) Biochem. J. 282, 919-927] is extended to the calculation of metabolite Concentration Control Coefficients. It is shown that the transient metabolite concentrations are related by a few algebraic equations, attributed to mass balance, stoichiometric constraints, quasi-equilibrium or quasi-steady states, and kinetic regulations. The coefficients in these relations can be estimated using linear regression, and can be used to calculate the Control Coefficients. The theoretical basis and two examples are discussed. Although the methodology is derived based on the linear approximation of enzyme kinetics, it yields reasonably good estimates of the Control Coefficients for systems with non-linear kinetics.

Quantification of the control of carbohydrate catabolism in the tapeworm Hymenolepis diminuta

1993 ◽  
Vol 71 (7-8) ◽  
pp. 315-323 ◽  
Author(s):  
Wendy Y. Precious ◽  
John Barrett
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Glycogen Synthase ◽  
Hymenolepis Diminuta ◽  
Rate Equations ◽  
Control Analysis ◽  
Control Coefficient ◽  
Flux Control ◽  
Flux Control Coefficients ◽  
Carbohydrate Catabolism ◽  
Control Coefficients

The elasticities for the different steps of carbohydrate catabolism in the tapeworm Hymenolepis diminuta were estimated from perturbation experiments. These data were then used to calculate flux and metabolite control coefficients. Enzyme elasticities were also calculated from the rate equations and an independent estimate of the flux control coefficients for phosphoenolpyruvate carboxykinase was made by inhibitor titration. The values obtained for the flux control coefficients for carbohydrate breakdown in H. diminuta are consistent with how the pathway is thought to be controlled in vivo. A sensitivity analysis of the flux control coefficients of the important regulatory enzymes in the pathway shows that for hexokinase, phosphofructokinase, pyruvate kinase, and phosphoenolpyruvate carboxykinase there are three or four key elasticities which have a significant effect on the coefficient. For glycogen synthase, the major factor in determining the magnitude of the flux control coefficient is the relative flux through the branch.Key words: Hymenolepis diminuta, metabolic control analysis, control coefficient, enzyme elasticity.

scholarly journals Metabolic control analysis. An application of signal flow graphs

1990 ◽  
Vol 269 (1) ◽  
pp. 141-147 ◽  
Author(s):  
A K Sen
Keyword(s):  
Feedback Inhibition ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Signal Flow Graph ◽  
Flow Graph ◽  
Signal Flow ◽  
Signal Flow Graphs ◽  
The Individual ◽  
Flow Graphs ◽  
Control Coefficients

In this paper the method of signal-flow graphs is used for calculating the Control Coefficients of metabolic pathways in terms of enzyme elasticities. The method is applied to an unbranched pathway (a) without feedback or feedforward regulation and (b) with feedback inhibition of the first enzyme by the last variable metabolite. It is shown that, by using a signal-flow graph, the control structure of a metabolic pathway can be represented in a graphical manner directly from the configuration of the pathway, without the necessity of writing the governing equations in a matrix form. From a signal-flow graph the various Control Coefficients can be evaluated in an easy and straightforward fashion without recourse to matrix inversion or other algebraic techniques. A signal-flow graph also provides a visual framework for analysing the cause-effect relationships of the individual enzymes.

scholarly journals A molecular investigation of genotype by environment interactions.

Genetics ◽  
1995 ◽  
Vol 139 (1) ◽  
pp. 19-33 ◽  
Author(s):  
A M Dean
Keyword(s):  
Genotype By Environment Interaction ◽  
Metabolic Control Analysis ◽  
Environment Interaction ◽  
Control Analysis ◽  
Genotype By Environment Interactions ◽  
Genotype By Environment ◽  
Natural Isolates ◽  
Selection Intensities ◽  
Beta Galactosidase ◽  
Control Coefficients

Abstract The fitnesses conferred by seven lactose operons, which had been transduced into a common genetic background from natural isolates of Escherichia coli, were determined during competition for growth rate-limiting quantities of galactosyl-glycerol, a naturally occurring galactoside. The fitnesses of these same operons have been previously determined on lactose and three artificial galactosides, lactulose, methyl-galactoside and galactosyl-arabinose. Analysis suggests that although marked genotype by environment interactions occur, changes in the fitness rankings are rare. The relative activities of the beta-galactosidases and the permeases were determined on galactosyl-glycerol, lactose, lactulose and methyl-galactoside. Both enzymes display considerable kinetic variation. The beta-galactosidase alleles provide no evidence for genotype by environment interactions at the level of enzyme activity. The permease alleles display genotype by environment interactions with a few causing changes in activity rankings. The contributions to fitness made by the permeases and the beta-galactosidases were partitioned using metabolic control analysis. Most of the genotype by environment interaction at the level of fitness is generated by changes in the distribution of control among steps in the pathway, particularly at the permease where large control coefficients ensure that its kinetic variation has marked fitness effects. Indeed, changes in activity rankings at the permease account for the few changes in fitness rankings. In contrast, the control coefficients of the beta-galactosidase are sufficiently small that its kinetic variation is in, or close to, the neutral limit. The selection coefficients are larger on the artificial galactosides because the control coefficients of the permease and beta-galactosidase are larger. The flux summation theorem requires that control coefficients associated with other steps in the pathway must be reduced, implying that the selection at these steps will be less intense on the artificial galactosides. This suggests that selection intensities need not be greater in novel environments.

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.

The use of in situ haemoglobin-free perfused liver in metabolic-control analysis

2000 ◽  
Vol 28 (2) ◽  
pp. 109-113 ◽  
Author(s):  
S. Soboll ◽  
G. C. Brown
Keyword(s):  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
Positive Control ◽  
Metabolic Control Analysis ◽  
Negative Control ◽  
Active State ◽  
Isolated Perfused Rat Liver ◽  
Control Analysis ◽  
High Control ◽  
Ion Pumping

In this study the network of ATP-consuming and -producing reactions, interacting via the cytosolic ATP/ADP + P1 system, was studied for the first time in an intact organ, the isolated perfused rat liver, using top-down metabolic-control analysis. Flux control in the metabolically resting state (only oxidative phosphorylation and ion pumps active) was only in the ATP-consumers, whereas in the metabolically active state (biosyntheses and ion-pumping ATPases active) most control over oxidative phosphorylation was in itself and some control was in ion-pumping ATPases. All ATP-consumers had high control over themselves, and ion-pumping ATPases had high negative control over the other ATP-consuming branches. Oxidative phosphorylation had high positive control over ATP-consuming reactions exept for ion-pumping ATPases. It is concluded that in the active state ATP-consumers compete for cytosolic ATP, but as the ion-pumping ATPases and oxidative phosphorylation are less sensitive towards the cytosolic ATP, other ATP-consumers have low control over these pathways.

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