Computational Systems Biochemistry Group

Introduction

Kinetic models are necessary to understand the dynamics of the cell metabolism. Therefore, a kinetic model of the core hepatocyte should be formulated, which includes energy and carbohydrate metabolism, amino acid synthesis and degradation, nucleotide metabolism and the detoxification of NH3.
The kinetic network should be able to show characteristic hepatocyte functions like

blood glucose homeostasis
NH3 detoxification
ketone body synthesis
protein synthesis

Metabolic Network Reconstruction

The core metabolism of the human hepatocyte was reconstructed [Fig. 1]. The resulting metabolic network is compartmentalized (cytosol, mitochondrion, blood) and consists of:

reactions 337
transporter 105
processes 22
regulations 123
compounds 180

Network Reconstruction and Validation

Information retrieval from databases (Brenda, Kegg, HumanCyc, Reactome)
Use of manually curated HepatoSys and textbook knowledge
Structural validation (removing dead ends, isolated reactions, ...)
Submodel creation and curation
Functional analysis (FBA)

Flux Balance Analysis (FBA)
FBA was used to validate the network. Sub networks of the full core model were created and different target fluxes optimized. In this process, the basic functionality of the network was tested.

Kinetic Model

Kinetic data collection
For all reactions in the model, the available kinetic data was obtained from databases (Sabio-RK [1], Brenda).

Rate laws

Detailed kinetic laws (if information available)
Generalized Michaelis Menten Kinetics (if kinetic data, but no rate laws available)
Otherwise mass action kinetics
Regulations are integrated with simple mechanisms

Only key regulatory reactions have to be modeled in full detail [2,3] to reproduce the kinetic behaviour of the network. For some pathways, detailed kinetic models have been developed in our group [4,5]. This information is used to build the full core metabolic network.

Work in progress
Working on test case glycolysis and gluconeogenesis (rate law formulation, integration of regulation and simulation). Applying the developed methods to all sub networks and the full core network in the future.

Researchers

Prof. Hermann-Georg Holzhütter
Sascha Bulik
Matthias König

This project is part of the HepatoSys Platform "Modeling" (SP 2.2: Kinetic Model of the Hepatocyte).

Presentation & Posters

HepatoSys Evaluation Meeting, Berlin, January, 2009
Presentation Subproject 2.2: Kinetic Model of the Hepatocyte [Pdf]

References

[1] Wittig U, Golebiewski M, Kania R, Krebs O, Mir S, Weidemann A, Anstein S, Saric J and Rojas I. (2006) SABIO-RK: Integration and Curation of Reaction Kinetics Data Lecture Notes in Bioinformatics, 4075:94-103 [WebLink]

[2] Bulik S, Grimbs S, Huthmacher C, Selbig J, Holzhütter HG. (2009) Kinetic hybrid models composed of mechanistic and simplified enzymatic rate laws: A promising method for speeding up the kinetic modelling of complex metabolic networks. FEBS Journal, 276:410-424 [PubMed]

[3] Grimbs S, Selbig J, Bulik S, Holzhütter HG, Steuer R. (2007) The stability and robustness of metabolic states: identifying stabilizing sites in metabolic networks. Mol Syst Biol., 3:146. [PubMed]

[4] Schuster R, Holzhutter HG. (1995) Use of mathematical models for predicting the metabolic effect of large-scale enzyme activity alterations. Application to enzyme deficiencies of red blood cells. Eur J Biochem., 229(2):403-18. [PubMed]

[5] Bartel T and Holzhütter HG. (1990) Mathematical modelling of the purine metabolism of the rat liver Biochim. Biophys. Acta, 1035, 331-339. [PubMed]

		Kinetic Model of Hepatocyte Metabolism
Home Research VirtualLiver People Publications Software Positions Events Contact		Introduction Kinetic models are necessary to understand the dynamics of the cell metabolism. Therefore, a kinetic model of the core hepatocyte should be formulated, which includes energy and carbohydrate metabolism, amino acid synthesis and degradation, nucleotide metabolism and the detoxification of NH3. The kinetic network should be able to show characteristic hepatocyte functions like blood glucose homeostasis NH3 detoxification ketone body synthesis protein synthesis Metabolic Network Reconstruction The core metabolism of the human hepatocyte was reconstructed [Fig. 1]. The resulting metabolic network is compartmentalized (cytosol, mitochondrion, blood) and consists of: reactions 337 transporter 105 processes 22 regulations 123 compounds 180 Network Reconstruction and Validation Information retrieval from databases (Brenda, Kegg, HumanCyc, Reactome) Use of manually curated HepatoSys and textbook knowledge Structural validation (removing dead ends, isolated reactions, ...) Submodel creation and curation Functional analysis (FBA) Flux Balance Analysis (FBA) FBA was used to validate the network. Sub networks of the full core model were created and different target fluxes optimized. In this process, the basic functionality of the network was tested. Kinetic Model Kinetic data collection For all reactions in the model, the available kinetic data was obtained from databases (Sabio-RK [1], Brenda). Rate laws Detailed kinetic laws (if information available) Generalized Michaelis Menten Kinetics (if kinetic data, but no rate laws available) Otherwise mass action kinetics Regulations are integrated with simple mechanisms Only key regulatory reactions have to be modeled in full detail [2,3] to reproduce the kinetic behaviour of the network. For some pathways, detailed kinetic models have been developed in our group [4,5]. This information is used to build the full core metabolic network. Work in progress Working on test case glycolysis and gluconeogenesis (rate law formulation, integration of regulation and simulation). Applying the developed methods to all sub networks and the full core network in the future. Researchers Prof. Hermann-Georg Holzhütter Sascha Bulik Matthias König This project is part of the HepatoSys Platform "Modeling" (SP 2.2: Kinetic Model of the Hepatocyte). Presentation & Posters HepatoSys Evaluation Meeting, Berlin, January, 2009 Presentation Subproject 2.2: Kinetic Model of the Hepatocyte [Pdf] References [1] Wittig U, Golebiewski M, Kania R, Krebs O, Mir S, Weidemann A, Anstein S, Saric J and Rojas I. (2006) SABIO-RK: Integration and Curation of Reaction Kinetics Data Lecture Notes in Bioinformatics, 4075:94-103 [WebLink] [2] Bulik S, Grimbs S, Huthmacher C, Selbig J, Holzhütter HG. (2009) Kinetic hybrid models composed of mechanistic and simplified enzymatic rate laws: A promising method for speeding up the kinetic modelling of complex metabolic networks. FEBS Journal, 276:410-424 [PubMed] [3] Grimbs S, Selbig J, Bulik S, Holzhütter HG, Steuer R. (2007) The stability and robustness of metabolic states: identifying stabilizing sites in metabolic networks. Mol Syst Biol., 3:146. [PubMed] [4] Schuster R, Holzhutter HG. (1995) Use of mathematical models for predicting the metabolic effect of large-scale enzyme activity alterations. Application to enzyme deficiencies of red blood cells. Eur J Biochem., 229(2):403-18. [PubMed] [5] Bartel T and Holzhütter HG. (1990) Mathematical modelling of the purine metabolism of the rat liver Biochim. Biophys. Acta, 1035, 331-339. [PubMed]