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Biomedical subjects

B N Kholodenko

Publications and source records attributed to B N Kholodenko.

At least 19 recordsLinked to original sources
PubMed1995

Calcium indirectly increases the control exerted by the adenine nucleotide translocator over 2-oxoglutarate oxidation in rat heart mitochondria.

The effect of calcium on the control exerted by the adenine nucleotide translocator over respiration in isolated heart mitochondria was investigated in order to determine whether calcium directly stimulates the translocator. At respiration rates intermediate between states 3 and 4, Ca2+ is shown to increase the control over 2-oxoglutarate oxidation exerted by the adenine nucleotide translocator in rat heart mitochondria. This did not occur when succinate was the respiratory substrate, even though the control exerted by the translocator was substantial, indicating that Ca2+ does not have a direct effect on the adenine nucleotide translocator. Ca2+ increased the uncoupled oxidation rate of 2-oxoglutarate, but not succinate. Using the summation theorem for flux control, the effect of Ca2+ is explained by a shift of the control over respiration rate toward the adenine nucleotide translocator, from the respiratory chain, presumably as the result of the activation of the 2-oxoglutarate dehydrogenase complex.

Adenosine Triphosphate↗
PubMed1995

Composite control of cell function: metabolic pathways behaving as single control units.

This paper shows that under some conditions the control exerted by a part of a metabolic network (a pathway) on a flux or concentration in any other part can be described through a single (overall) control coefficient. This has the following implications: (i) the relative contributions of a pathway enzyme to the regulation of the pathway (output) flux and of any flux or concentration outside are identical; therefore, the control analysis of the pathway 'in isolation' allows one to determine the control exerted by any pathway enzyme on the rest of the cell by estimation of the control efficient of just one, arbitrarily chosen enzyme; (ii) the relative control of any two metabolic variables outside the pathway (measured as the ratio of the control coefficients over these two variables outside) is the same for all pathway enzymes. These properties allow one to substitute effectively a pathway by a single (super)reaction and make it possible to consider such a pathway as a metabolic unit within the cellular enzyme network.

Cells↗
PubMed1995

Control theory of metabolic channelling.

Various factors appear to control muscle energetics, often in conjunction. This calls for a quantitative approach of the type provided by Metabolic Control Analysis for intermediary metabolism and mitochondrial oxidative phosphorylation. To the extent that direct transfer of high energy phosphates and spatial organization plays a role in muscle energetics however, the standard Metabolic Control Theory does not apply, neither do its theorems regarding control. This paper develops the Control Theory that does apply to the muscle system. It shows that direct transfer of high energy phosphates bestows a system with enhanced control: the sum of the control exerted by the participating enzymes on the flux of free energy from the mitochondrial matrix to the actinomyosin may well exceed the 100% mandatory for ideal metabolic pathways. It is also shown how sequestration of high energy phosphates may allow for negative control on pathway flux. The new control theory gives method functionally to diagnose the extent to which channelling and metabolite sequestration occur.

Animals↗
PubMed1995

The macroworld versus the microworld of biochemical regulation and control.

Our understanding of cell physiology has been helped greatly by viewing metabolism as a set of reactions catalysed by independent catalysts (enzymes) in ideal solutions. Yet the differences between this idealized cell and reality have strong implications for biochemical regulation and control. We show here that in the real cell an enzyme controls cell physiology in more than a single way. These different controlling modes in the real 'macroworld' can be related to one another by implementing a new type of control analysis, which is formulated in terms of the 'microworld' of the elemental processes.

Cells↗
PubMed1995

Coenzyme cycles and metabolic control analysis: the determination of the elasticity coefficients from the generalised connectivity theorem.

Metabolic control analysis allows one to express the elasticity coefficients (which describe the "local" kinetic features of enzymes) in terms of the control coefficients (quantitative indicators of the "global" control properties). However, when coenzymes (or metabolites linked by conservation constraints) are present in the pathway this procedure yields the "apparent" values of elasticity coefficients that correspond to the kinetic responses of the enzymes to such a simultaneous change of the coenzyme forms which leaves the total concentration of these forms unchanged (e.g., NAD+ + NADH in the glycolysis). We show that a generalised connectivity theorem (Kholodenko et al, Eur. J. Biochem. (1994) 225, 179-186) makes it possible to express the elasticity coefficients with respect to every coenzyme form separately. Such expressions include (i) the control coefficients and (ii) the responses to changes in the total concentrations of the coenzymes.

Coenzymes↗
PubMed1992

Control of the metabolic flux in a system with high enzyme concentrations and moiety-conserved cycles. The sum of the flux control coefficients can drop significantly below unity.

In a number of metabolic pathways enzyme concentrations are comparable to those of substrates. Recently it has been shown that many statements of the 'classical' metabolic control theory are violated if such a system contains a moiety-conserved cycle. For arbitrary pathways we have found: (a) the equation connecting coefficients CEiJ (obtained by varying the Ei concentration) and CviJ (obtained by varying the kicat), and (b) modified summation equations. The sum of the enzyme control coefficients (equal to unity under the 'classical' theory) appears always to be below unity in the systems considered. The relationships revealed were illustrated by a numerical example where the sum of coefficients CEiJ reached negative values. A method for experimental measurements of the above coefficients is proposed.

Enzymes↗
PubMed1991

[Regulation of the heart mitochondrial respiration rate. Comparison of oxidation of succinate and NAD-dependent substrates].

Regulation of respiration at all rates between State 4 and State 3 was studied in heart mitochondria oxidizing FAD- and NAD-dependent substrates (succinate, pyruvate + + malate and palmitoylcarnitine). The creatine phosphokinase ADP-regenerating system was used which allows to fix the concentrations of extramitochondrial adenine nucleotides in such a way that the rate of respiration is controlled by mitochondrial processes alone. It was shown that respiration is controlled by delta mu(H+)-utilizing system within the respiration rate interval from State 4 till 70-80% of the maximal rate in State 3 (corresponding to physiological rates) both for NAD- and FAD-dependent substrates. The main step in the control of respiration near State 4 is proton leakage through the inner mitochondrial membrane, whereas in all the other parts of the mentioned interval this role is assigned to the adenine nucleotide translocator (ANT). The control coefficient for ANT is higher, while that of proton leakage is lower at the same relative rates of respiration with NAD-dependent substrates compared with succinate. These differences were found to be related to much higher values of the membrane potential generated at the same relative rates of succinate oxidation in comparison with the case with pyruvate + + malate. The contribution of delta mu(H+)-utilizing system to respiration control sharply decreases, whereas that of the delta mu(H+)-generating system increases at maximal rates of respiration near State 3. This phenomenon in more characteristic of succinate. In this case the control coefficient of ANT drops to zero, while that of succinate dehydrogenase rises to 0.7.

Adenine Nucleotides↗
PubMed1989

[The role of long-chain acyl-CoA in the disturbances of oxidative phosphorylation in the myocardium].

The effect of intramitochondrial acyl-CoA on the respiration of rabbit heart mitochondria in different metabolic states was studied. Acyl-CoA inhibited O2 consumption by 11% in State 4 and by 6% in State 3. However, the effect of acyl-CoA was more pronounced (20%) in the intermediate state of respiration between State 4 and State 3. The data obtained suggest that acyl-CoA can regulate oxidative phosphorylation in heart mitochondria in vivo.

Acyl Coenzyme A↗
PubMed1988

How do external parameters control fluxes and concentrations of metabolites? An additional relationship in the theory of metabolic control.

The flux through a metabolic pathway can be controlled by external signals from the environment. These signals are formally described as changes in external parameters, such as concentrations of external metabolites (substrates or effectors) or physical parameters, e.g. temperature, pH, ionic strength. It was proved that the response coefficient of the flux (or of the concentration) to a change in an external parameter is the weighted average of external elasticities of pathway enzymes towards this parameter; weight factors are the control coefficients of corresponding enzymes. As compared with the previously known relationships these ones are applicable to the more common case of parameters acting on more than one enzyme. Along with other applications, the use of the obtained relationships for control analysis of moiety-conserved cycles is considered.

Adenosine Diphosphate↗
PubMed1988

[The role of adenine nucleotide translocator in the regulation of oxidative phosphorylation in heart mitochondria].

The regulatory role of adenine nucleotide translocase in oxidative phosphorylation was determined by titration of respiration of isolated rabbit heart mitochondria with carboxyatractyloside in the creatine phosphokinase ADP-regenerating system, which is not rate-limiting. It was found that the respiration rate is not controlled by adenine nucleotide translocase in states 3 and 4. Within the physiological region of respiration (30-70% of the maximal rate), the control coefficient for ADP/ATP translocase is 0.62-0.75. Thus, translocase plays a key role in the regulation of oxidative phosphorylation.

Animals↗
PubMed1984

Control of mitochondrial oxidative phosphorylation.

The objective of this investigation is to analyze the two following problems of the regulation of mitochondrial oxidative phosphorylation: what is the extramitochondrial parameter that controls ATP production according to the cytoplasmic demands and how the control is distributed between various mitochondrial enzymes. On the basis of the data of Groen et al. (1982) it is shown that as the respiration rates ranged over 30-50% of the maximum (i.e. within the physiological region) the contribution of the adenine nucleotide translocator to the control of the ATP flux is no less than 90%, referring to the total contribution of all mitochondrial enzymes as 100%. Founding on the key role of the adenine nucleotide translocator it has been concluded that besides the extramitochondrial [ATP]/[ADP] ratio the absolute ADP concentration is another extramitochondrial signal controlling significantly the rate of oxidative phosphorylation.

Adenosine Diphosphate↗
PubMed1982

Dynamic stability of steady states and static stabilization in unbranched metabolic pathways.

The paper is concerned with the conditions of dynamic (asymptotic) stability of steady states in unbranched metabolic pathways. The stationary flux in such pathways is generally determined by the concentration of the end product due to the effector action of this product on the reactions proceeding in its synthetic pathway. The delay in feedback circuits causes violation of dynamic stability at large static stabilization factors. A methods permitting analytic estimation of the critical stabilization factor is suggested. Sufficient and necessary conditions for asymptotic stability of the steady state in the general case of the pathway with a single feedback loop have been established. Mechanisms for maintenance of the steady state asymptotic stability at large static stabilization factors are studied. It has been shown that the range of dynamic stability can be widened greatly, if the pathway contains one or two reactions (but not more) of relatively small effective rate constants. Short strong negative feedback is also found to extend considerably the range of dynamic stability of the pathway. The feedback is more effective if it acts on the reaction with small effective rate constant.

Feedback↗
PubMed1981

Regulation of glycolysis in human erythrocytes. The mechanism of ATP concentration stabilization.

The mathematical modelling of human erythrocyte energy metabolism has shown that stabilization of ATP concentration can be achieved if the curve representing the relation between glycolysis rate and ATP concentration (glycolysis characteristic) is bell-shaped with steeply descending part at physiologically normal ATP concentration. The glycolysis characteristic of human erythrocytes has been obtained experimentally. In erythrocytes of different donors the glycolysis characteristics are greatly different quantitatively, but have qualitatively similar bel-like shape with steeply descending part at physiologically normal ATP concentration. This characteristics can be made coincident for all donors if they are plotted in relative units taking for 100% the physiologically normal values of glycolysis rate and ATP for every individual donor. The coincidence of the normalized erythrocyte glycolysis characteristics for different donors can be achieved in the mathematical model of erythrocyte energy metabolism under the assumption that the phosphofructokinase rate depends effectively on the relation of ATP to adenylate pool and the total erythrocyte ATPase is strongly inhibited by AMP.

Adenosine Triphosphate↗
PubMedDate not supplied

Control theory of metabolic channelling.

Various factors appear to control muscle energetics, often in conjunction. This calls for a quantitative approach of the type provided by Metabolic Control Analysis for intermediary metabolism and mitochondrial oxidative phosphorylation. To the extent that direct transfer of high energy phosphates and spatial organization plays a role in muscle energetics however, the standard Metabolic Control Theory does not apply, neither do its theorems regarding control. This chapter develops the Control Theory that does apply to the muscle system. It shows that direct transfer of high energy phosphates bestows a system with enhanced control: the sum of the control exerted by the participating enzymes on the flux of free energy form the mitochondrial matrix to the actinomyosin may well exceed the 100% mandatory for ideal metabolic pathways. It is also shown how sequestration of high energy phosphates may allow for negative control on pathway flux. The new control theory gives methods functionally to diagnose the extent to which channelling and metabolite sequestration occur.

Animals↗
PubMedDate not supplied

[Quantitative model of human erythrocyte glycolysis. I. Relationship between the stationary rate of glycolysis and the ATP concentration].

A mathematical model is presented of the Embden--Meyerhof pathway in the human red blood cell. The rate of the system stationary flux is determined by the first part of the chain including three enzymatic reactions. The function has been calculated which describes the dependence of the stationary rate of glucose consumption and ATP production on the concentration of ATP. The curve has a bell shape with the physiological normal point situated in the descending segment. The descending segment is a result of the inhibition of the phosphofructokinase by ATP and the strong inhibition of the hexokinase by glucose-6-phosphate.

Adenosine Triphosphate↗