Regulating the cellular economy of supply and demand

Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
FEBS Letters (Impact Factor: 3.17). 07/2000; 476(1-2):47-51. DOI: 10.1016/S0014-5793(00)01668-9
Source: PubMed


Cellular metabolism is a molecular economy that is functionally organised into supply and demand blocks linked by metabolic products and cofactor cycles. Supply-demand analysis allows the behaviour, control and regulation of metabolism as a whole to be understood quantitatively in terms of the elasticities of supply and demand, which are experimentally measurable properties of the individual blocks. The kinetic and thermodynamic aspects of regulation are clearly distinguished. One important result is the demonstration that when flux is controlled by one block, the other block determines to which degree the concentration of the linking metabolite is homeostatically maintained.

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Available from: Jan-Hendrik Servaas Hofmeyr, Sep 30, 2014
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    • "Feedbacks in general can have various effects on a dynamical system. They may increase the robustness of a pre-existing attractor, making a change of steady state more difficult, or stabilise more rapidly a new steady state after a perturbation (see for example Rosen 1970; 1976; Savageau 1976; Fell 1997; Hofmeyr and Cornish-Bowden 2000).They may also lead to oscillations (Savageau 1976) or induce instabilities, by amplifying (through non-linear positive loops) microscopic fluctuations around bifurcation points, like it typically occurs in developmental processes (Rosen 1976). "
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    ABSTRACT: Biological regulation is what allows an organism to handle the effects of a perturbation, modulating its own constitutive dynamics in response to particular changes in internal and external conditions. With the central focus of analysis on the case of minimal living systems, we argue that regulation consists in a specific form of second-order control, exerted over the core (constitutive) regime of production and maintenance of the components that actually put together the organism. The main argument is that regulation requires a distinctive architecture of functional relationships, and specifically the action of a dedicated subsystem whose activity is dynamically decoupled from that of the constitutive regime. We distinguish between two major ways in which control mechanisms contribute to the maintenance of a biological organisation in response to internal and external perturbations: dynamic stability and regulation. Based on this distinction an explicit definition and a set of organisational requirements for regulation are provided, and thoroughly illustrated through the examples of bacterial chemotaxis and the lac-operon. The analysis enables us to mark out the differences between regulation and closely related concepts such as feedback, robustness and homeostasis.
    Biology and Philosophy 08/2015; DOI:10.1007/s10539-015-9497-8 · 1.19 Impact Factor
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    • "To study optimal enzyme usage in general, one needs to know how enzyme levels (as control variables) act on the stationary fluxes and metabolite levels. For steady states under small perturbations, this relation is described by metabolic control coefficients [7] [8]. These coefficients, in turn, are related to optimal enzyme profiles. "
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    ABSTRACT: Metabolic systems are governed by a compromise between metabolic benefit and enzyme cost. This hypothesis and its consequences can be studied by kinetic models in which enzyme profiles are chosen by optimality principles. In enzyme-optimal states, active enzymes must provide benefits: a higher enzyme level must provide a metabolic benefit to justify the additional enzyme cost. This entails general relations between metabolic fluxes, reaction elasticities, and enzyme costs, the laws of metabolic economics. The laws can be formulated using economic potentials and loads, state variables that quantify how metabolites, reactions, and enzymes affect the metabolic performance in a steady state. Economic balance equations link them to fluxes, reaction elasticities, and enzyme levels locally in the network. Economically feasible fluxes must be free of futile cycles and must lead from lower to higher economic potentials, just like thermodynamics makes them lead from higher to lower chemical potentials. Metabolic economics provides algebraic conditions for economical fluxes, which are independent of the underlying kinetic models. It justifies and extends the principle of minimal fluxes and shows how to construct kinetic models in enzyme-optimal states, where all enzymes have a positive influence on the metabolic performance.
    • "Conversely, overexpression of a gene often fails to bring about an increase in flux through a pathway (Morandini 2009) due to a lack of sufficient flux control or to regulation of that enzyme. There has also been a widely held obsession with so-called " rate limiting " or " committed " steps in metabolism, and the conventional wisdom is that control of flux resides in such reactions with large negative Gs. Apart from the fact that G applicable in the cellular environment is often confused with unrealistic G o values (reactants all 1 M and at pH 7), these reactions are, in fact, rare (Morandini 2009), and more commonly the control of flux through a pathway is actually distributed over many of the steps (Hofmeyr & Cornish-Bowden 2000) with the consequence that no one enzyme control coefficient is very high. Reactions with a large negative G actually require tight control to prevent them running to completion, which would deplete the reactants and accumulate the products, possibly to unacceptable levels (Morandini 2009). "
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    Sugarcane: Physiology, Biochemistry, and Functional Biology, 12/2013: pages 483-520; , ISBN: 9780813821214
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