bulik3

Title

Kinetic hybrid models composed of mechanistic and simplified enzymatic rate laws – a promising method for speeding up the kinetic modelling of complex metabolic networks

Authors

Sascha Bulik (1), Sergio Grimbs (2), Carola Huthmacher (1), Joachim Selbig (2,3) and Hermann G. Holzhütter (1)

Affiliations

1 Institute of Biochemistry, Charité – University Medicine Berlin, Germany 2 Department of Bioinformatics, Max-Planck-Institute for Molecular Plant Physiology, Potsdam-Golm, Germany 3 Institute of Biochemistry and Biology, University of Potsdam, Germany

Abstract

Kinetic modelling of complex metabolic networks – a central goal of com- putational systems biology – is currently hampered by the lack of reliable rate equations for the majority of the underlying biochemical reactions and membrane transporters. On the basis of biochemically substantiated evi- dence that metabolic control is exerted by a narrow set of key regulatory enzymes, we propose here a hybrid modelling approach in which only the central regulatory enzymes are described by detailed mechanistic rate equations, and the majority of enzymes are approximated by simplified (nonmechanistic) rate equations (e.g. mass action, LinLog, Michaelis– Menten and power law) capturing only a few basic kinetic features and hence containing only a small number of parameters to be experimentally determined. To check the reliability of this approach, we have applied it to two different metabolic networks, the energy and redox metabolism of red blood cells, and the purine metabolism of hepatocytes, using in both cases available comprehensive mechanistic models as reference standards. Identi- fication of the central regulatory enzymes was performed by employing only information on network topology and the metabolic data for a single reference state of the network [Grimbs S, Selbig J, Bulik S, Holzhutter HG & Steuer R (2007) Mol Syst Biol 3, 146, doi:10.1038/msb4100186]. Calculations of stationary and temporary states under various physiological challenges demonstrate the good performance of the hybrid models. We propose the hybrid modelling approach as a means to speed up the devel- opment of reliable kinetic models for complex metabolic networks.

Journal

FEBS Journal 276 (2009) 410–424

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Global parameters

Local parameters

Assignment rules

Rate rules

Algebraic rules