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Metabolic control analysis FAQ

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

Introduction

This page is intended as an elementary introduction to metabolic control analysis for people who have heard of metabolic control analysis but have very little idea of what it is. If you need something more advanced you should try Pedro Mendes’s MCA Web, the web version of Chapter 12 of Fundamentals of Enzyme Kinetics, (3rd edition, 2004). Many of the answers give links to more detailed information to be found on other pages. Strictly the title FAQ (frequently asked questions) may be a misnomer, as really I have little idea of how often some of these questions are asked; the page is more an attempt to answer the sort of questions I would ask if I were new to the subject. Suggestions for additional questions will be welcome, as will comments, corrections, etc. to the answers that are listed.

Although the questions are grouped approximately according to subject matter, the answers are deliberately listed in an arbitrary order. This is to encourage browsing, as in an reference book, where one sometimes discovers information by chance that is much more interesting than the answer to the question that provoked taking the book off the shelves in the first place.

Index

What is metabolic control analysis?

Metabolic control analysis is a method for analysing how the control of fluxes and intermediate concentrations in a metabolic pathway is distributed among the different enzymes that constitute the pathway. Instead of assuming the existence of a unique rate-limiting step, it assumes that there is a definite amount of flux control and that this is spread quantitatively among the component enzymes. Metabolic control analysis was formerly (and is sometimes still) known as metabolic control theory, and is closely related to the engineering discipline known as sensitivity analysis. Alternative approaches to studying the kinetic behaviour of multi-enzyme systems are flux-oriented theory and biochemical systems theory.

What is the connectivity relationship?

For any metabolite and any flux in a system, one can multiply the flux control coefficient of an enzyme by its elasticity with respect to the metabolite concerned. If one does this for all of the enzymes in the system and adds all the resulting products, they give a sum of zero. This is the general form of the connectivity relationship.

For metabolites that have non-zero elasticities for numerous enzymes (i.e. for metabolites that influence the activities of numerous enzymes) the resulting sum contains many terms and is not particularly useful. However, if a metabolite influences only two enzymes, as for example the enzyme that produces it and the enzyme that consumes it, it will have only two non-zero elasticities, and the sum will contain only two terms, each of which must then be minus the other. In this case the connectivity relationship becomes much more useful, as it provides a way of calculating an unknown control coefficient from a known one, provided the relevant elasticities are also known.

What is an elasticity coefficient?

An elasticity coefficient is exactly the same as an elasticity; both terms are used.

What is metabolic control theory (and is it different from metabolic control analysis)?

Metabolic control theory is an older term for metabolic control analysis. It is still used by some authors, but started to fall into disuse at the end of the 1980s when some authors began to emphasize that metabolic control analysis is more a method for analysing how control is distributed than a body of theory as such.

How is metabolic control analysis
related to sensitivity analysis?

Sensitivity analysis is a technique in engineering that shares much of the mathematics and concepts of metabolic control analysis. The control coefficients of metabolic control analysis are, in effect, sensitivities as understood by engineers.

Why does metabolic control analysis appear to
ignore enzyme mechanisms?

Metabolic control analysis tends to treat the kinetic properties of the component enzymes as a black box. Some authors have been very critical of this, suggesting that shedding light on mechanism is the only reason for studying kinetics in the first place. However, in reality it is the usual kind of abstraction one finds (and needs) at all level of science. Although wave mechanics is at the basis of all chemistry, it is hardly possible to present a list of typical reactions of aldehydes, for example, in terms of wave equations. Even if it were possible it would not be helpful because it would hide the points of immediate interest in a lot of algebra. At another level, all interactions between living organisms are dependent on the laws of chemistry, but again, it would be neither possible nor, if it were possible, helpful to discuss the political relationships between countries in terms of chemical reactions. Studies of biochemical kinetics have been dominated for nearly a century by an interest in molecular mechanisms, but for understanding how whole pathways behave it has been found useful to decrease the emphasis on mechanism. Thus mechanisms such as cooperative feedback inhibition are not ignored in metabolic control analysis, but they are given less emphasis than in classical studies of metabolic regulation.

Where can I find more detailed information on the web?

Some possibilities are as follows: