Enzyme, metabolic control theory

The object of metabolic control theory is to provide a sound mathematical foundation for the quantitative estimation of the role played by individual enzymes on the control of flux through a metabolic pathway and also the control exerted by individual enzymes on the concentration of intermediate metabolites in the pathway. The general principles of metabolic control theory and biochemical systems theory can be visualized by considering the simple metabolic pathway in Fig. 6. The numbers above the arrows... 

Those of us that have done basic research have tended to look at enzyme activity, pathway activity, hormone and receptor concentrations and the like. That is fine, and we have learned from that, but in many oases we did not consider the underlying controls (transcription rates, enzyme synthesis rates) or did not fully relate the cellular information to the animal production level in any systematic mathematical formalism. The former is difficult to do, expensive, and in many ways not necessary to our purposes in animal agriculture. The latter is easy to do, inexpensive and in fact an absolute requirement for our purposes what are the true biological controls, at the level at which control is exerted, that drive animal production. A description of metabolic control theory and control coefficients is beyond the purpose of this article, but readers are at least encouraged to read some of Kacser, Carson and Cobelli and Comish-Bowden to understand this (Comish-Bowden, 2005). I will go into more detail with references on multiple regressions to study the relationship of basic metabolic control, transcriptomics and animal production below. 

Bottom-up systems biology does not rely that heavily on Omics. It predates top-down systems biology and it developed out of the endeavors associated with the construction of the first mathematical models of metabolism in the 1960s [10, 11], the development of enzyme kinetics [12-15], metabolic control analysis [16, 17], biochemical systems theory [18], nonequilibrium thermodynamics [6, 19, 20], and the pioneering work on emergent aspects of networks by researchers such as Jacob, Monod, and Koshland [21-23]. 

Westerhoff, H. V. Chen, Y. D. How do enzyme activities control metabolite concentrations An additional theorem in the theory of metabolic control. Eur J Biochem 1984,142 425-430. 

Metabolic control analysis (MCA) is a specialized theory that is concerned with particular sensitivity coefficients, elasticity coefficients and control coefficients. These coefficients tell us how a steady state of a biochemical system shifts in response to perturbation in enzyme activities or external (clamped) substrate concentration [53, 209],... 

Sorribas, A. Savageau, M. A. (1989a). A comparison ofvariant theories of intact biochemical systems 1 Enzyme-enzyme interactions and biochemical systems theory. Math. Biosci. 94, 161-193. Sorribas, A. Savageau, M. A. (1989b). A comparison of variant theories of intact biochemical systems 2 Flux oriented and metabolic control theaies. Math. Biosci. 94,195-238. 

The developed control theory for metabolic systems allows inferring of, for example, the effects of local changes, like the properties of an enzyme on global properties as the flux through the system. Furthermore, general global properties of the systems were captured by summation and connectivity theorems, see [5] for a comprehensive review. 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

The 1950s saw a change in emphasis from the analysis of bio-chemistry-as-kinetics to that of biochemistry-as-information. The theoretical rationale for this transition was provided by the growth of the new sciences associated with the development of computers. Theories of control , feedback , and information transfer were collated in 1948 by the American engineer and mathematician Norbert Wiener under the name of cybernetics. As more and more became known about the mechanisms of individual enzymic reactions, about their energy-requirements, and about the workings of series of enzymes in the harmony of metabolic pathways, biochemists seized on these new concepts in order to probe the ways in which the cell controlled and regulated its own metabolism how, so to speak, it decided at any one time... 

Where complex properties occur in living systems, as for example in chaotic cardiac arrhythmias, they are characteristic of pathological failure of the normal controls— in this case in some kinds of heart disease—not of health. Even at the level of an individual enzyme, the enzyme peroxidase from horseradishes, an example of chaotic behavior has been known for many years, but we have no idea how its properties benefit the horseradish, and they contribute nothing to our present understanding of how metabolic systems are controlled in general. The sort of positive feedback loops that account for the complex behavior of economic systems, political relations, and indeed some aspects of biology such as the extravagant overdevelopment of the peacock s tail, are conspicuously absent from the major pathways in the metabolic economy. There is no reason, therefore, to see any contradiction in the claim that classical economic theory works much better in metabolism than it does in the domain in which it was developed. 

The former theory that the primary effect consists in a direct interaction with certain enzymes (perhaps in the manner that vitamins act as components of coenzymes) has not been upheld for most hormones. Examples of quick responding metabolic regulation, such as the control of l lood glucose, depend in all likelihood on permeability changes of cell membranes. Another mechanism of action is seen in the stimulation of specific gene loci (Clever and Karlson). This promotes the production of messenger RNA and ultimately the synthesis of specific enzymes. The mechanism resembles that of enzyme induction in bacteria (cf. Fig. and also Chapt. VII-7). 

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