Control theory of metabolic channelling

Abstract

Various factors appear to control muscle energetics, often in conjunction. This calls for a quantitative approach of the type provided by Metabolic Control Analysis for intermediary metabolism and mitochondrial oxidative phosphorylation. To the extent that direct transfer of high energy phosphates and spatial organization plays a role in muscle energetics however, the standard Metabolic Control Theory does not apply, neither do its theorems regarding control. This paper develops the Control Theory that does apply to the muscle system. It shows that direct transfer of high energy phosphates bestows a system with enhanced control: the sum of the control exerted by the participating enzymes on the flux of free energy from the mitochondrial matrix to the actinomyosin may well exceed the 100% mandatory for ideal metabolic pathways. It is also shown how sequestration of high energy phosphates may allow for negative control on pathway flux. The new control theory gives methods functionally to diagnose the extent to which channelling and metabolite sequestration occur. (Mol Cell Biochem 143: 151-168, 1995)

Energy, control and DNA structure in the living cell

“…Recently Kholodenko and colleagues [21,22,31] developed a new way to analyze control, i.e. by considering the modulation of elemental steps.…”

“…Pathways in which enzyme concentrations are high with respect to metabolite concentrations have special control properties when the metabolites are subject to moiety conservation [21,28,29,30]). In cases of enzyme-enzyme interactions as well as in other "non-simple" pathways [31] there is a difference between the control coefficients defined in terms of modulations of activity and those defined in terms of modulations of the enzyme concentration [116]. Both definitions are important since they refer to different experimental methods of determining the control coefficients [32,33].…”

Systems biology towards life in silico: mathematics of the control of living cells

“…The summation laws apply to any metabolic network with the sometimes confusing or inspiring effect that control of a flux through a pathway may well lie in the network outside that pathway [21]. The laws also apply to pathways that are not ideal in the sense that more than one enzyme is involved in a single reaction [23] or metabolites are channeled between enzymes [27]. MCA also applies to signal transduction and gene expression pathways where it is indeed worthwhile further to extend the analysis to Hierarchical Control Analysis [25,39].…”

Composite control of cell function: metabolic pathways behaving as single control units

“…Hierarchical and modular analysis [14,15] relaxed the restriction that subsystems must be connected by only a single intermediate. Kholodenko [10,16] focussed on the conditions under which the control coefficients as determined within a pathway would coincide, after scaling, with the control coefficients as measured in the entire metabolic network. Such an invariance of the relative distribution of the control allowed one to determine a single ('overall' [17,18]) control coefficient of that pathway in a unique and unambiguous way.…”

“…Such an invariance of the relative distribution of the control allowed one to determine a single ('overall' [17,18]) control coefficient of that pathway in a unique and unambiguous way. The ideas of how control exerted by pathway enzymes on the rest of the cell depends on the links between this pathway and its surroundings [10,16] and the implications of this type of modular organization of cellular metabolism were, however, not elaborated in details. In the present paper we revisit the ideas considered in [10,16] and show under what conditions a whole pathway can be regarded as a metabolic unit (super-reaction) within enzyme networks of the cell.…”