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Introduction to Metabolic Control Analysis (MCA)

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The Handbook of Metabolomics

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Metabolic Control Analysis (MCA) provides a conceptual framework for understanding the control of fluxes though metabolic pathways at the molecular level. It further provides a theoretical underpinning for an experimental approach to determining metabolic control. In this chapter, the basic principles of MCA are introduced, and the kinds of applications that are accessible to this approach. The relationship to flux analysis and measurement of metabolic fluxes is outlined.

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Author information

Authors and Affiliations

  1. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Maliackal Poulo Joy & Timothy C. Elston

  2. Departments of Medicine and Chemistry, Center for Regulatory and Environmental Analytical Metabolomics (CREAM), and James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Andrew N. Lane

  3. Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Jeffrey M. Macdonald

  4. Department of Biochemistry and Molecular Biology, Associated Unit to CSIC, Institute of Biomedicine of University of Barcelona (IBUB) and IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain

    Marta Cascante

Authors
  1. Maliackal Poulo Joy
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  2. Timothy C. Elston
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  3. Andrew N. Lane
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  4. Jeffrey M. Macdonald
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  5. Marta Cascante
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Corresponding author

Correspondence to Andrew N. Lane .

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Louisville, Louisville, Kentucky, USA

    Teresa Whei-Mei Fan

  2. Structural Biology Program, University of Louisville, Louisville, Kentucky, USA

    Andrew N. Lane

  3. Department of Chemistry, University of Louisville, Louisville, Kentucky, USA

    Richard M. Higashi

Glossary

Disequilibrium ratio

Deviation of a reaction from equilibrium as expressed by the ratio of the actual reactants to the values they have at equilibrium, under the prevailing conditions Γ = (p/s)/Keq. This is related to the available free energy difference for driving a reaction: ΔG = ΔG 0−RTln Γ

Elasticity

Is a property of an enzyme and determines how the flux through a particular step depends on the substrate concentration: ∂lnv i/∂lns i

Flux

Net rate of a reaction or of a pathway. Flux is the difference between the forward rate and the reverse rate, J = v f−v r

Flux Control

The extent to which flux is determined and is a system property. If J is the net flux, the control is determined by the sensitivity of the net flux to changes in activity at individual steps

Flux Control Coefficient (FCC)

Fractional change in flux due to a fractional change in enzyme activity a: FCC = ∂lnJ/∂lna

Hill equation

Proteins that interact with multiple substrates or ligands, such as hemoglobin, may show cooperativity between binging sites. The Hill equation represents an all or none cooperative binding equation of the form F = s n/(K + s n) where n is the Hill coefficient. A value n > 1 implies positive cooperativity, and n < 1 is negative cooperativity. N is always less than the number of binding sites. Cf. Monod–Wyman–Changeux and Koshland–Nemethy–Filmer models (15)

k cat, K m

In the Michaelis–Menten mechanism, k cat is the turnover number for an enzyme and represents the apparent first order rate constant for the breakdown of ES complexes. K m is operationally the concentration of substrate at which the reaction velocity is half its maximum possible, as determined by V max = k cat.[enzyme]. k cat/K m is the apparent second order rate constant or substrate-enzyme complex formation and determines the specificity of the enzyme for its substrate (15)

Rate

Speed of a reaction. For a Michaelis–Menten reaction, the initial rate is v i  = V max.s/(K m + s)

Regulation

In MCA, control and regulation are distinct properties. Control is defined through the coefficients such as FCC. In contrast, regulation refers to the maintenance of homeostasis (i.e., resistance change), and a regulated enzyme is one that performs this task. Such an enzyme does not have to have a high FCC

Response

How flux changes with respect to a local parameter p such as an effector Ri = ∂lnJ/∂lnpi

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Joy, M.P., Elston, T.C., Lane, A.N., Macdonald, J.M., Cascante, M. (2012). Introduction to Metabolic Control Analysis (MCA). In: Fan, TM., Lane, A., Higashi, R. (eds) The Handbook of Metabolomics. Methods in Pharmacology and Toxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-618-0_9

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  • DOI: https://doi.org/10.1007/978-1-61779-618-0_9

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-617-3

  • Online ISBN: 978-1-61779-618-0

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