Application of electrical analogues for control analysis of simple metabolic pathways.
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ABSTRACT:
SUBMITTER: Sen AK
PROVIDER: S-EPMC1149657 | biostudies-other | 1990 Nov
REPOSITORIES: biostudies-other
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Project description:In this paper the method of signal-flow graphs is used for calculating the Control Coefficients of metabolic pathways in terms of enzyme elasticities. The method is applied to an unbranched pathway (a) without feedback or feedforward regulation and (b) with feedback inhibition of the first enzyme by the last variable metabolite. It is shown that, by using a signal-flow graph, the control structure of a metabolic pathway can be represented in a graphical manner directly from the configuration of the pathway, without the necessity of writing the governing equations in a matrix form. From a signal-flow graph the various Control Coefficients can be evaluated in an easy and straightforward fashion without recourse to matrix inversion or other algebraic techniques. A signal-flow graph also provides a visual framework for analysing the cause-effect relationships of the individual enzymes.
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Project description:Metabolic control analysis is a powerful technique for the evaluation of flux control within biochemical pathways. Its foundation is the elasticity coefficients and the flux control coefficients (FCCs). On the basis of a thermokinetic description of reaction rates it is here shown that the elasticity coefficients can be calculated directly from the pool levels of metabolites at steady state. The only requirement is that one thermodynamic parameter be known, namely the reaction affinity at the intercept of the tangent in the inflection point of the curve of reaction rate against reaction affinity. This parameter can often be determined from experiments in vitro. The methodology is applicable only to the analysis of simple two-step pathways, but in many cases larger pathways can be lumped into two overall conversions. In cases where this cannot be done it is necessary to apply an extension of the thermokinetic description of reaction rates to include the influence of effectors. Here the reaction rate is written as a linear function of the logarithm of the metabolite concentrations. With this type of rate function it is shown that the approach of Delgado and Liao [Biochem. J. (1992) 282, 919-927] can be much more widely applied, although it was originally based on linearized kinetics. The methodology of determining elasticity coefficients directly from pool levels is illustrated with an analysis of the first two steps of the biosynthetic pathway of penicillin. The results compare well with previous findings based on a kinetic analysis.
| S-EPMC1218046 | biostudies-other
Project description:BackgroundOptimality principles have been used to explain the structure and behavior of living matter at different levels of organization, from basic phenomena at the molecular level, up to complex dynamics in whole populations. Most of these studies have assumed a single-criteria approach. Such optimality principles have been justified from an evolutionary perspective. In the context of the cell, previous studies have shown how dynamics of gene expression in small metabolic models can be explained assuming that cells have developed optimal adaptation strategies. Most of these works have considered rather simplified representations, such as small linear pathways, or reduced networks with a single branching point, and a single objective for the optimality criteria.ResultsHere we consider the extension of this approach to more realistic scenarios, i.e. biochemical pathways of arbitrary size and structure. We first show that exploiting optimality principles for these networks poses great challenges due to the complexity of the associated optimal control problems. Second, in order to surmount such challenges, we present a computational framework which has been designed with scalability and efficiency in mind, including mechanisms to avoid the most common pitfalls. Third, we illustrate its performance with several case studies considering the central carbon metabolism of S. cerevisiae and B. subtilis. In particular, we consider metabolic dynamics during nutrient shift experiments.ConclusionsWe show how multi-objective optimal control can be used to predict temporal profiles of enzyme activation and metabolite concentrations in complex metabolic pathways. Further, we also show how to consider general cost/benefit trade-offs. In this study we have considered metabolic pathways, but this computational framework can also be applied to analyze the dynamics of other complex pathways, such as signal transduction or gene regulatory networks.
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Project description:We present a method for logical analysis of signal-transduction networks, focusing on metabolic and mitogenic signalling by the insulin receptor, with specific emphasis on dependence of the signalling properties on the timing of binding events. We discuss a basic model which demonstrates this dependence (hormone binding leads to activation of the receptor which can lead to a commitment to mitogenic signalling), and show how residence time of the hormone on the receptor can determine the specificity of signalling between the alternative metabolic or mitogenic pathways. The method gives conditions for the selection of specific branches in the signalling pathway expressed in terms of inequalities among the characteristic activation or deactivation times of components of that pathway. In this way, the conditions for mitogenic signalling can be given in terms of a required range of values of the hormone residence time on the receptor, which is directly related to the kinetic dissociation rate.
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Project description:BackgroundIt is a daunting task to identify all the metabolic pathways of brain energy metabolism and develop a dynamic simulation environment that will cover a time scale ranging from seconds to hours. To simplify this task and make it more practicable, we undertook stoichiometric modeling of brain energy metabolism with the major aim of including the main interacting pathways in and between astrocytes and neurons.ModelThe constructed model includes central metabolism (glycolysis, pentose phosphate pathway, TCA cycle), lipid metabolism, reactive oxygen species (ROS) detoxification, amino acid metabolism (synthesis and catabolism), the well-known glutamate-glutamine cycle, other coupling reactions between astrocytes and neurons, and neurotransmitter metabolism. This is, to our knowledge, the most comprehensive attempt at stoichiometric modeling of brain metabolism to date in terms of its coverage of a wide range of metabolic pathways. We then attempted to model the basal physiological behaviour and hypoxic behaviour of the brain cells where astrocytes and neurons are tightly coupled.ResultsThe reconstructed stoichiometric reaction model included 217 reactions (184 internal, 33 exchange) and 216 metabolites (183 internal, 33 external) distributed in and between astrocytes and neurons. Flux balance analysis (FBA) techniques were applied to the reconstructed model to elucidate the underlying cellular principles of neuron-astrocyte coupling. Simulation of resting conditions under the constraints of maximization of glutamate/glutamine/GABA cycle fluxes between the two cell types with subsequent minimization of Euclidean norm of fluxes resulted in a flux distribution in accordance with literature-based findings. As a further validation of our model, the effect of oxygen deprivation (hypoxia) on fluxes was simulated using an FBA-derivative approach, known as minimization of metabolic adjustment (MOMA). The results show the power of the constructed model to simulate disease behaviour on the flux level, and its potential to analyze cellular metabolic behaviour in silico.ConclusionThe predictive power of the constructed model for the key flux distributions, especially central carbon metabolism and glutamate-glutamine cycle fluxes, and its application to hypoxia is promising. The resultant acceptable predictions strengthen the power of such stoichiometric models in the analysis of mammalian cell metabolism.
| S-EPMC2246127 | biostudies-literature
Project description:We introduce STAMPS, a pathway-centric web service for the development of targeted proteomics assays. STAMPS guides the user by providing several intuitive interfaces for a rapid and simplified method design. Applying our curated framework to signaling and metabolic pathways, we reduced the average assay development time by a factor of ?150 and revealed that the insulin signaling is actively controlled by protein abundance changes in insulin-sensitive and -resistance states. Although at the current state STAMPS primarily contains mouse data, it was designed for easy extension with additional organisms.
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Project description:BackgroundIn eukaryotes, the cell is divided into several compartments enclosed by unitary membranes. Such compartmentalization is critical for cells to restrict different pathways to be carried out in different subcellular regions. The summary and classification of subcellular localizations of metabolic pathways are the first steps towards understanding their roles in spatial differentiation and the specialization of metabolic pathways in different organisms.ResultsIntegrating the subcellular localization of enzymes and their pathways from UniProt Knowledgebase and KEGG pathway databases, we present the first database for subcellular localization of 43014 pathways from 80676 UniProt entries and their pathway annotations from UniProt and KEGG pathway databases. To extract pathway localization across organisms, we defined 889 superpathways as clusters of basic pathways with the same pathway annotations from different organisms. Over eighty-eight percent of superpathways in the Swiss-Prot dataset occur in cytoplasm and mitochondria. And over seventy percent of UniProt superpathways have multiple localization annotations. We summarized four common reasons for the multiple localization of superpathways. Based on this database, we also discovered 88 potential transport systems between different steps of multiply localized pathways and 45 duplicated genes from 17 pathways, occurring in parallel in several locations in humans.ConclusionsPathLocdb is a free web-accessible database that enables biochemical researchers to quickly access summarized subcellular localization of pathways from UniProt and KEGG pathway databases. As the first effort to systematically integrate pathway localization, this database is very useful in discovering the variation of localization of pathways between organisms and also cross-talk between different organelles within a pathway. The Pathlocdb database is available at http://pathloc.cbi.pku.edu.cn.
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Project description:A novel approach, based on geotracer compositional correlation analysis is reported, which reveals the oil charge sequence and migration pathways for five oil fields in Saudi Arabia. The geotracers utilised are carbazoles, a family of neutral pyrrolic nitrogen compounds known to occur naturally in crude oils. The approach is based on the concept that closely related fields, with respect to filling sequence, will show a higher carbazole compositional correlation, than those fields that are less related. That is, carbazole compositional correlation coefficients can quantify the charge and filling relationships among different fields. Consequently, oil migration pathways can be defined based on the established filling relationships. The compositional correlation coefficients of isomers of C1 and C2 carbazoles, and benzo[a]carbazole for all different combination pairs of the five fields were found to vary extremely widely (0.28 to 0.94). A wide range of compositional correlation coefficients allows adequate differentiation of separate filling relationships. Based on the established filling relationships, three distinct migration pathways were inferred, with each apparently being charged from a different part of a common source kitchen. The recognition of these charge and migration pathways will greatly aid the search for new accumulations.
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