Regulatory systems, kinetic

R. Thomas, ed, Kinetic logic A Boolean approach to the analysis of complex regulatory systems, Lecture Notes in Biomathematics, Vol. 29, Springer-Verlag, Berlin, 507 pp. 

An attempt was made recently to find out how sensitively the regulatory system that controls the cell cycle and cell proliferation responds to signal input. Ferrell et found that, in intact oocytes, the response is ultrasensitive , a kinetic characterization introduced by Daniel E. Koshland Jr.26 (Ultrasensitivity has been defined as the response of an enzyme that is more sensitive to changes in the concentration of the substrate than an enzyme with a normal hyperbolic response, according to the Michaelis-Menten equation. One can also use the Hill coefficient (wh) to indicate hyperbolic (Michaelis-Menten) sensitivity ( h = 1-0), ultrasensitivity ( h > l)j and subsensitivity ( h <... 

The tertiary metabolites seem to be devoid of any special biological activity of their own. They may conceivably be rendered active by mutations affecting their precursors and in this way gain access to the main biochemical events. If this happens they must eventually be subjected to regulatory systems such as enzymatic intervention. Their introduction into metabolic processes and their new activity demands means of regulation other than purely kinetic and thermodynamic control. 

Dagaut, P., Gail, S. Chemical kinetic study of the effect of a biofuel additive on Jet-Al combustion. J. Phys. Chem. A 111, 3992-4000 (2007) de Jong, H. Modeling and simulation of genetic regulatory systems a literature review. J. Comput. Biol. 9, 67-103 (2002)... 

A large number of amino acid transporters have been detected by isolating mutations which selectively inactivate one permease without altering enzyme activities involving the corresponding amino acid. Competitive inhibition, kinetics and regulatory behaviour have also been used as criteria to distinguish one transport system from another (see section 4.2). 

Manipulation of one enzymatic step in a system can have wide reaching consequences because of the interplay between metabolite levels and a wide range of regulatory circuits. These circuits can operate at the level of transcription, translation, post-translational modification, or through allosteric and competitive influences on the kinetic properties of enzymes. 

This section mainly builds upon classic biochemistry to define the essential building blocks of metabolic networks and to describe their interactions in terms of enzyme-kinetic rate equations. Following the rationale described in the previous section, the construction of a model is the organization of the individual rate equations into a coherent whole the dynamic system that describes the time-dependent behavior of each metabolite. We proceed according to the scheme suggested by Wiechert and Takors [97], namely, (i) to define the elementary units of the system (Section III. A) (ii) to characterize the connectivity and interactions between the units, as given by the stoichiometry and regulatory interactions (Sections in.B and II1.C) and (iii) to express each interaction quantitatively by... 

It is clear from both Figs. 8.20 and 8.21 that CTP acts as an inhibitor while ATP acts as an activator. It is now established that both CTP and ATP bind to the regulatory binding site, which differs from the catalytic sites. The remarkable similarity between the equilibrium Bis on the one hand and the kinetic data on the other hand confirms the assertion made at the beginning of this chapter, that allosteric effects can be studied in equilibrated systems. 

The book is organized in nine chapters and eleven appendices. Chapters 1 and 2 introduce the fundamental concepts and definitions. Chapters 3 to 7 treat binding systems of increasing complexity. The central chapter is Chapter 4, where all possible sources of cooperativity in binding systems are discussed. Chapter 8 deals with regulatory enzymes. Although the phenomenon of cooperativity here is manifested in the kinetics of enzymatic reactions, one can translate the description of the phenomenon into equilibrium terms. Chapter 9 deals with some aspects of solvation effects on cooperativity. Here, we only outline the methods one should use to study solvation effects for any specific system. 

In the course of time open systems that exchange matter and energy with then-environment generally reach a stable steady state. However, as shown by Glansdorff and Prigogine, once the system operates sufficiently far from equilibrium and when its kinetics acquire a nonlinear nature, the steady state may become unstable [15, 18]. Feedback regulatory processes and cooperativity are two major sources of nonlinearity that favor the occurrence of instabilities in biological systems. 

Further extensions of the model are required to address the dynamical consequences of these additional regulatory loops and of the indirect nature of the negative feedback on gene expression. Such extended models have been proposed for Drosophila [112, 113] and mammals [113]. The model for the circadian clock mechanism in mammals is schematized in Fig. 3C. The presence of additional mRNA and protein species, as well as of multiple complexes formed between the various clock proteins, complicates the model, which is now governed by a system of 16 or 19 kinetic equations. Sustained or damped oscillations can occur in this model for parameter values corresponding to continuous darkness. As observed in the experiments on the mammalian clock. Email mRNA oscillates in opposite phase with respect to Per and Cry mRNAs [97]. The model displays the property of entrainment by the ED cycle... 

Currently, there are no validated and regulatory accepted in vitro methods for assessing repeated dose toxicity. Numerous in vitro systems have been developed over the last decades and have been discussed and summarized in recent ECVAM reports on repeated dose toxicity testing (Worth and Balls 2002, Prieto et al. 2005, Prieto et al. 2006). Human in vitro data, particularly on kinetics and metabolism, and in vitro test data from well-characterized target organ and target system models on, e.g., mode of action(s)/mechanism(s) of toxicity may be useful in the interpretation of observed repeated dose toxicity. 

Regulatory enzymes containing multiple polypeptide chains are just beginning to be understood in molecular terms. Considerably more thermodynamic, kinetic, and structural information is required. Several multienzyme complexes are available in a reasonably pure state, but the molecular characterization of their mechanisms is still in a rather primitive state. The situation is even more difficult with membrane-bound enzymes. A few of these enzymes can be obtained as well-defined entities, but in many cases purification of the enzyme system and all its components is quite far off in the future. The small quantity of material usually available is also a great problem with these systems. As might be... 

Decreasing recycle flow has the opposite effects. Temperatures increase, pressure decreases, and the heat transfer coefficients decrease. Thus the cooled reactor system has some inherent self-regulatory properties that make it openloop-stable, at least for the set of kinetic and design parameters used in this example. Later in this chapter, a hot reaction system will be discussed that has a higher activation energy and larger specific reaction rate. As we will see, this new system is openloop-unstable. 

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