By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. It appears able to predict different effects of the two types of drug on cells with different expression levels and consequently different effects on the generation of resistance. Optimally complexes are assembled in a strict order and new histone modifications sensitize the chromatin for the formation of the next complex. Therefore, it is unclear which metabolic process or group of processes should be activated to increase growth rate. We have illustrated that, in silico, one can do so in principle. The dysregulated metabolites we identified were leucine, phenylalanine, lysine, cysteine, aspartic acid, glycerol-3-phosphate and the vitamin precursor to coenzyme A. This should be particularly relevant for enzyme kinetics where the substrate is an enzyme, such as in phosphorelay and mitogen-activated protein kinase pathways.
Use of the adaptive model to analyze the functioning of the glutathione network revealed that a threshold input concentration of methionine may be required for effective detoxification of reactive metabolites by glutathione conjugation. We show that kinetic parameters, which are usually tedious to determine, are not required in the calculations. A target enzyme may exist in two states, an active state and an inactive state. We present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. We determined systematically the extent to which the enzyme activities depend on the concentrations of the adenine nucleotides. Noise and heterogeneity Section 9 - Dealing with Systems Biology Research: - Neil W. As a result of increases in the prevalences of obesity, insulin resistance, and hyperlipidemia, the number of people with hepatic steatosis continues to increase.
The authors will discuss a theoretical framework addressing such integrated systems. The inset provides an overview of the regulatory interactions. The fermentative capacity was lower in cells grown under respiratory conditions than in cells grown under respirofermentative conditions, yet more resilient to prolonged nitrogen starvation. Equations derived from detailed mechanistic models for each inhibition were fitted to the experimental data. The in- sensitivity of a network to external perturbations results from the interplay between network dynamics, structure, and enzyme kinetics.
We hypothesized that the lack of correspondence could be due to upregulation of expression of glutamyl cysteine synthetase, one of the enzymes controlling glutathione synthesis, and confirmed this experimentally. We choose to keep the mathematical detail minimal and highlight a number of concepts and approaches that are emerging in the analysis of molecular networks. Ophthalmic acid and 5-oxoproline are metabolites involved in glutathione metabolism, which can be measured readily in the blood and urine and have been proposed as candidate biomarkers of hepatic glutathione content. The apparent equilibrium constant K' for a biochemical reaction is written in terms of such sums of species and can be used to calculate standard transformed Gibbs energies of reaction Δ r G'°. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness.
Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. One of the major attempts at silicon cell systems biology, in the Manchester Centre for Integrative Systems Biology, is discussed in some detail. An effector regulates the activity of the target enzyme indirectly by activating modifying enzyme 1 , inhibiting modifying enzyme 2 , or both. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation.
Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. Often, in living cells different molecular species compete for binding to the same molecular target. The duration of the entire transcription cycle can easily become tens of minutes, even though single proteins reside on the chromatin for only tens of seconds. Furthermore, the availability of extensive kinetic data on all glycolytic enzymes has led to the early development of a complete, experiment-based dynamic model of an important biochemical pathway. Our model correctly predicted that hepatic glutathione depletion following paracetamol administration resulted in elevated concentrations of 5-oxoproline and ophthalmic acid in blood and of 5-oxoproline in urine. However, currently it is unclear whether their concentrations in plasma exhibit a robust correlation with hepatic glutathione content. Experimental strategies are applied to establish a set of in vivo concentrations for isoenzymes and metabolites.
The cellular growth rate is controlled by a variety of processes. Here, we construct a generic minimal model of the genetic regulatory network controlling cell fate determination, which exhibits five elementary characteristics of cell differentiation: stability, directionality, branching, exclusivity, and promiscuous expression. Adopting systems biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial origin. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. We conclude this review by sketching how the various systems biology tools may help in the various phases of drug development in the pharmaceutical industry. Chapter 2: Real-time kinetic assay technologies for characterising enzymes in metabolic pathways. For a few frequently occurring network motifs we show how they manage noise.
It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. The columns represent the mean of four biological replicates high steatosis versus two biological replicates low steatosis. Increase in sugar or refined carbohydrate consumption results in an increase of insulin and insulin resistance that can lead to the accumulation of fat in the liver. In general, life at high temperature requires very efficient adaptation to temperature changes, which is most difficult to deal with for organisms, and it is unclear how biological networks can withstand and respond to such changes. Living cells are bound to notice that metabolic engineering is being effected, through changes in metabolite concentrations. A The average flux through glutathione synthetase the final step in glutathione synthesis.