Igor Goryanin

The systems biology markup language (SBML) : a medium for representation and exchange of biochemical network models

MOTIVATIONnMolecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively.nnnRESULTSnWe summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others.nnnAVAILABILITYnThe specification of SBML Level 1 is freely available from http://www.sbml.org/

The impact of the regulatory design on the response of epidermal growth factor receptor‐mediated signal transduction towards oncogenic mutations

Epidermal growth factor receptor (EGFR)‐mediated signal transduction is often hyperactivated in tumour cells and therefore considered a promising target for cancer therapy. A number of computational models have been developed which describe the pathway in great detail. These models are similar in their description of the activation events. The deactivation of the EGFR signalling seems to be cell type‐specific and is less understood. Deactivation via receptor internalization, feedback inhibition of son of sevenless (SOS) by double phosphorylated, extracellular signal‐regulated kinase (ERKPP) or transiently activated Ras‐GTPase activating protein (Ras‐GAP) proteins is discussed to play a role. In this study we address the question of to what extent the effect of oncogenic perturbations on EGFR signalling depend on the specific regulation structure. This is investigated using a detailed pathway model under two regulatory modes: the negative feedback via ERKPP to SOS and feed‐forward deactivation via transiently activated Ras‐GAP proteins. We show that the effect of receptor overexpression differs qualitatively under both regulations. In the system with transiently activated Ras‐GAP it may result in an attenuation of the ERK activation. Such a nonintuitive effect was also observed experimentally. In general we find the model with transiently activated Ras‐GAP to have a higher robustness towards receptor overexpression and Ras mutations. In particular, we demonstrate that this model can compensate for these oncogenic perturbations if the regulation is strong. The negative feedback can not protect the system against Ras mutations. A general sensitivity analysis, however, shows a higher robustness of the model under negative feedback, indicating the limited significance of such analyses for the prediction of specific oncogenic perturbations.

A computer model of the gene network of the cholesterol biosynthesis regulation in the cell: analysis of the effect of mutations

Gene network is an ensemble of genes expressed in a coordinated mode that controls a vital function of the organism [1]. In this work, we studied the gene network of the cholesterol biosynthesis regulation in the cell and its exchange with the blood plasma cholesterol. A computer model of the dynamics of the gene network function based on a generalized chemical-kinetic simulation method was designed [2]. The model is described in terms of elementary processes (biochemical reactions). The optimal set of values of the parameters used in this model is determined. We performed digital simulation of the dynamic characteristics of the gene network responses to the effects exerted on the system in the normal state and in the case of mutations. The sensitivity of the steady-state content of free cholesterol in the cell to the mutationinduced changes occurring in the rates of molecular processes in the gene network was analyzed. We showed that mutations affecting the regulatory processes to the greatest extent influence the steady-state concentration of free cholesterol in the cell.

Kinetic model of imidazologlycerol-phosphate synthetase from Escherichia coli.

Based on the available experimental data, we developed a kinetic model of the catalytic cycle of imidazologlycerol-phosphate synthetase from Escherichia coli accounting for the synthetase and glutaminase activities of the enzyme. The rate equations describing synthetase and glutaminase activities of imidazologlycerol-phosphate synthetase were derived from this catalytic cycle. Using the literature data, we evaluated all kinetic parameters of the rate equations characterizing individually synthetase and glutaminase activities as well as the contribution of each activity depending on concentration of the substrates, products, and effectors. As shown, in the presence of 5′-phosphoribosylformimino-5-aminoimidazolo-4-carboxamideribonucleotide (ProFAR) and imidazologlycerol phosphate (IGP) glutaminase activity dominates over synthetase activity at sufficiently low concentrations of 5′-phosphoribulosylformimino-5-aminoimidazolo-4-carboxamideribonucleotide (PRFAR). Increased PRFAR concentrations resulted in decreased contribution of glutaminase activity and, consequently, increased the contribution of synthetase activity in the enzyme functioning.

Kinetic Modelling as a Modern Technology to Explore and Modify Living Cells

We describe a general strategy that enables us to develop kinetic models of large-scale metabolic systems by collecting and using all available metabolic experimental data. Our approach can be used to explore the local and global regulatory properties of selected metabolic pathways, and to predict how cell genome modifications can meet selected biotechnological and biomedical criteria. We have applied the strategy for the development and use of detailed kinetic models of catabolic and anabolic pathways of E. coli and mitochondrial energy metabolism.