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Metabolic control analysis FAQ

This page is the last of four containing a list of frequently asked questions (FAQ) about metabolic control analysis.

Where can I find more detailed information in the printed literature?

The two classic papers that introduced metabolic control analysis are those of Kacser and Burns (1973) and Heinrich and Rapoport (1974). The former has recently been reissued in a revised form (Kacser, Burns and Fell, 1995) that is probably more appropriate for the modern reader, both because it is more easily accessible and because it is expressed in the terminology currently in use.

Two monographs mainly concerned with metabolic control analysis are those of Fell (1997) and Heinrich and Schuster (1996), of which the former is fairly elementary and the latter fairly advanced. (I have reviewed both of these.) Chapter 12 of the book on enzyme kinetics by Cornish-Bowden (1995a) is concerned with metabolic control analysis, and is available as hypertext.

Multiauthor books edited by Cornish-Bowden and Cárdenas (1990, 2000) contain almost complete pictures of metabolic control analysis as it was in 1989 and 1999. (The 1990 book also includes some chapters on biochemical systems theory and a brief account of flux-oriented theory).

The issue of the Journal of Theoretical Biology for 7th October 1996 is a special issue in memory of Henrik Kacser, and contains many contributions concerned with current applications of metabolic control analysis. Abstracts of all of the contributions are available on the web.

Two reviews of metabolic control analysis are those of Fell (1992) and Cornish-Bowden (1995).

A collection of references to reviews on channelling and related topics is available on the web.

What is a control coefficient?

A control coefficient is the system property of an enzyme that expresses how some systemic variable, usually a flux or a metabolite concentration, depends on the activity of the enzyme. If some perturbation of an enzyme activity increases the rate of the isolated reaction by 5%, whereas the same perturbation of the same enzyme when it is embedded in a metabolic system increases the flux by 2%, the enzyme is said to have a flux control coefficient of 2/5, or 0.4. If the same perturbation causes the concentration of the substrate of the enzyme to decrease by 10%, the enzyme has a concentration control coefficient for that metabolite of -10/5, or -2.

Notice that there is no mention of the concentration of the enzyme when the control coefficients are defined in this way. However, the rate of an enzyme-catalysed reaction is often found to be directly proportional to the enzyme concentration: if (and only if) this is the case the anonymous perturbation referred to in the definition can be a change in the enzyme concentration. This then allows a less abstract and apparently simpler definition of a control coefficient, and such a definition was widely used for a number of years. It is, however, falling into disuse, both because it is not always valid, and because even when it is valid it can encourage the wholly erroneous misconception that metabolic control analysis deals only with effects brought about by changes in enzyme concentration or limiting activity.

In the older literature control coefficients were known as sensitivities or control strengths.

How does channelling affect the summation relationships?

The term channelling refers to mechanisms in which the product of one enzyme is transferred directly to an enzyme that uses it as substrate without necessarily passing through the free solution. This implies the existence of a complex between the two (or more) enzymes involved, a static complex if it has a long life time and exists independently of whether the reaction is proceeding, or a dynamic complex if it is formed transiently during the catalysis. In either case increasing the concentration of one component enzyme of the complex affects the concentrations both of the free component and those of any complexes that it forms with other enzymes. As these various different species may have different kinetic constants for the reactions in which they are involved the rate of the reaction catalysed by the enzyme whose total concentration is varied will not be proportional to that concentration.

As long as the summation relationships are expressed in terms of control coefficients that refer to the independent catalysts, in accordance with modern practice, they are not affected by channelling. As it is no longer true that the individual rates are proportional to the concentrations of the individual enzymes, however, the summation relationships no longer apply if the control coefficients refer to enzyme concentrations rather than catalytic activities. With static complexes the deviations may be large, but with dynamic complexes they still usually apply approximately.

What is biochemical systems theory?

Biochemical systems theory is an approach developed by M. A. Savageau and his associates, who regard it as a general theory of metabolic control that includes metabolic control analysis and flux-oriented theory as special cases. It places much more emphasis on predicting how systems will behave when the conditions are changed than on understanding in physical terms how they are controlled.

How is metabolic control analysis related to
classical ideas of metabolic regulation?

Because of the abstraction of mechanistic details into the elasticities of metabolic control analysis, the classical concepts of feedback inhibition of the first committed step of a pathway, cooperativity, etc., can seem to be forgotten about, or at least hidden as mathematical details. However, their effects on the distribution of control have been well understood (albeit not much emphasized) since the original paper of Kacser and Burns (1973).

Is it true that metabolic control analysis assumes
that enzymes are regulated solely by changing
their concentrations (or V values)?

No! This is a serious misconception that has bedevilled understanding of metabolic control analysis for years. It arose from the once-common practice of defining control coefficients in terms of changes of enzyme concentration. However, the modern practice is to regard control coefficients defined in this way as response coefficients (for response to changes in enzyme concentration) that may happen to be numerically equal to control coefficients only because the relevant elasticities are equal to 1. In any case, the partitioned response property means that the magnitude of the response of a system to any effector is determined by the elasticity of the enzyme acted on by the effector with respect to that effector multiplied by the control coefficient for that enzyme.

How does metabolic control analysis explain the fact that
most mutations in diploid organisms are recessive?

In a diploid organism the usual possibilities for the degree of expression of an enzyme are 100% (normal homozygote), 50% (heterozygote) and 0% (abnormal homozygote) of the activity in the normal homozygote. However, the flux control coefficients of most enzymes are close to zero, and although they increase if the enzyme activity is decreased they rarely increase to significant levels if the activity decrease is 50% or less. Thus heterozygotes, with only 50% activity of the affected enzyme, can maintain essentially the same metabolic fluxes as individuals with 100% activity. However, if an enzyme activity falls to zero its flux control coefficient for the flux through its own reaction becomes 1, as the capacity to supply flux through the pathway in question vanishes. Thus although heterozygotes typically display little or no phenotypic difference from normal homozygotes, abnormal homozygotes display the phenotype characteristic of the complete loss of a metabolic pathway.

References

Only sources specifically referred to are listed here. To find where any reference is cited, follow the link indicated by [@] that follows it. A longer list is given with the web version of Chapter 12 of the 3rd (2004) edition of Fundamentals of Enzyme Kinetics, and other references may be found in the articles listed.