Metabolism models

Figure 10.3-23. Metabolic model of glycolysis and tbe pentose phosphate pathway in E. coli. Squares Indicate enzyme activities circles indicate regulatory effects,...

Models for batch culture can be constructed by assuming mechanisms for each phase of the cycle. These mechanisms must be reasonably comph-cated to account for a lag phase and for a prolonged stationary phase. Unstructured models treat the cells as a chemical entity that reacts with its environment. Structured models include some representation of the internal cell chemistry. Metabolic models focus on the energy-producing mechanisms within the cells. 

This paper explores how models may be developed to account for the relationship between the stable isotope composition of a body tissue of an organism and its diet. The main approach taken is to express this relationship as an explicit equation, or a DIFF , and then to show how the values of such a DIFF can be evaluated from published experimental data. These values can be expected to have a much wider meaning than a simple encapsulation of a particular experimental design. As a main example, we show how the values may be used to constract a metabolic model in which the synthesis of non-essential amino acid for collagen construction can be treated. A second example is to show how the evaluation, in terms of diet, of the spacing between collagen and carbonate 6 C may be put on a rigorous basis. 

Schilling CH, Covert MW, Famili I, Church GM, Edwards JS, Palsson BO. Genome-scale metabolic model of Helicobacter pylori 26695. J Bacteriol 2002 184 4582-93. 

Absorption of americium is greater in iron deficient animals than in iron replete adult animals (Sullivan and Ruemmler 1988 Sullivan et al. 1986) (see Section 3.4.1.2). Concurrent oral exposure to Fe3+ and americium also appears to increase the absorption of ingested americium the latter effect may result from redox reactions in the gastrointestinal tract catalyzed by Fe3+ (Sullivan et al. 1986). These differences are accounted for in the discussions and dosimetric/metabolic models of the ICRP (1989, 1993) and the NEA (1988). 

Durbin PW, Schmidt CT. 1985. PartV Implications for metabolic modeling. Health Phys 49(4) 623-661. 

Eisele GR, Bernard SR, Nestor CW. 1987. Gastrointestinal absorption of americium-241 by orally exposed swine Comparison of experimental results with predictions of metabolic models. Radiat Res 112 62-73. 

Mewhinney JA, Griffith WC, Muggenburg BA. 1979. Comparison of metabolic models used to describe the fate of inhaled 241Am02 based on inhalation studies in the beagle dog. Health Phys 37(6) 830. 

Harley NH, Kneip TH. 1985. An integrated metabolic model for lead in humans of all ages. Final report to the US Environmental Protection Agency. Contract No. B44899 with New York University School of Medicine. Department of Environmental Medicine, 1-14. 

The evidence cited here is only a very small sample of the vast quantity of research into putative cognitive enhancers. However, many of these compounds that have demonstrated positive effects are believed to influence cerebral metabolism, whether through increased blood flow, glucose metabolism or other indirect routes, as outlined above. Furthermore, these metabolic effects are hypothesised to be at least partly responsible for the cognitive improvements documented. Indeed, many of the putative cognitive enhancers currently available claim modes of influence (Table 14.1) that would fall in line with a metabolic model of cognitive enhancement. 

Challenges of using Rodents as Drug Metabolism Models... 

Probably the most straightforward and well-known approach to metabolic modeling is to represent metabolic processes in terms of ordinary differential... 

Figure 2. Current mathematical representations of metabolism utilize a hierarchy of descriptions, involving different levels of detail and complexity. Current approaches to metabolic modeling exhibit a dichotomy between large and mostly qualitative models versus smaller, but more quantitative models. See text for details. The figure is redrawn from Ref. 23. See color insert.

These differences probably contribute to the fact that mathematical modeling is, as yet, not seen as a mainstream research tool in many areas of molecular biology. However, as will be described in the remainder of this chapter, many obstacles in the construction of kinetic models of cellular metabolism can be addressed using a combination of novel and established experimental and computational techniques, enabling the construction of metabolic models of increasing complexity and size. 

Aiming to construct explicit dynamic models, Eqs. (5) and (6) provide the basic relationships of all metabolic modeling. All current efforts to construct large-scale kinetic models are based on an specification of the elements of Eq (5), usually involving several rounds of iterative refinement For a schematic workflow, see again Fig. 4. In the following sections, we provide a brief summary of the properties of the stoichiometric matrix (Section III.B) and discuss the most common functional form of enzyme-kinetic rate equations (Section III.C). A selection of explicit kinetic models is provided in Table I. TABLE I Selected Examples of Explicit Kinetic Models of Metabolisin 1 ... 

For the quantitative description of the metabolic state of a cell, and likewise which is of particular interest within this review as input for metabolic models, experimental information about the level of metabolites is pivotal. Over the last decades, a variety of experimental methods for metabolite quantification have been developed, each with specific scopes and limits. While some methods aim at an exact quantification of single metabolites, other methods aim to capture relative levels of as many metabolites as possible. However, before providing an overview about the different methods for metabolite measurements, it is essential to recall that the time scales of metabolism are very fast Accordingly, for invasive methods samples have to be taken quickly and metabolism has to be stopped, usually by quick-freezing, for example, in liquid nitrogen. Subsequently, all further processing has to be performed in a way that prevents enzymatic reactions to proceed, either by separating enzymes and metabolites or by suspension in a nonpolar solvent. 

Importantly, when interpreting the results obtained from a metabolic model, we always have to take into account the source and thus the reliability of the data that were used to parameterize these models. In the usual case that tissues and compartments are mixed in the sampling procedures, interpretation has to be limited to phenomena that are not influenced by the averaging effect. 

Specifically, SKM seeks to overcome several known deficiencies of stoichiometric analysis While stoichiometric analysis has proven immensely effective to address the functional capabilities of large metabolic networks, it fails for the most part to incorporate dynamic aspects into the description of the system. As one of its most profound shortcomings, the steady-state balance equation allows no conclusions about the stability or possible instability of a metabolic state, see also the brief discussion in Section V.C. The objectives and main requirements in devising an intermediate approach to metabolic modeling are as follows, a schematic summary is depicted in Fig. 25 ... 

Within this contribution, our aim was to summarize and describe the ways and means of modelmaking. In our opinion, and reflecting the structure of this contribution, the construction and analysis of metabolic models rests upon five main pillars (i) The expertise and knowledge of classic biochemistry, defining the building blocks and their interactions (as described in Section III). 

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