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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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
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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
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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
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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)
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Fractional change in flux due to a fractional change in enzyme activity a: FCC = ∂lnJ/∂lna
- Hill equation
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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
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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
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Speed of a reaction. For a Michaelis–Menten reaction, the initial rate is v i = V max.s/(K m + s)
- Regulation
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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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