A method for estimation of elasticities in metabolic networks using steady state and dynamic metabolomics data and linlog kinetics.
BACKGROUND
Dynamic modeling of metabolic reaction networks under in vivo conditions is a crucial step in order to obtain a better understanding of the (dis)functioning of living cells. So far dynamic metabolic models generally have been based on mechanistic rate equations which often contain so many parameters that their identifiability from experimental data forms a serious problem. Recently, approximative rate equations, based on the linear logarithmic (linlog) format have been proposed as a suitable alternative with fewer parameters.


RESULTS
In this paper we present a method for estimation of the kinetic model parameters, which are equal to the elasticities defined in Metabolic Control Analysis, from metabolite data obtained from dynamic as well as steady state perturbations, using the linlog kinetic format. Additionally, we address the question of parameter identifiability from dynamic perturbation data in the presence of noise. The method is illustrated using metabolite data generated with a dynamic model of the glycolytic pathway of Saccharomyces cerevisiae based on mechanistic rate equations. Elasticities are estimated from the generated data, which define the complete linlog kinetic model of the glycolysis. The effect of data noise on the accuracy of the estimated elasticities is presented. Finally, identifiable subset of parameters is determined using information on the standard deviations of the estimated elasticities through Monte Carlo (MC) simulations.


CONCLUSIONS
The parameter estimation within the linlog kinetic framework as presented here allows the determination of the elasticities directly from experimental data from typical dynamic and/or steady state experiments. These elasticities allow the reconstruction of the full kinetic model of Saccharomyces cerevisiae, and the determination of the control coefficients. MC simulations revealed that certain elasticities are potentially unidentifiable from dynamic data only. Addition of steady state perturbation of enzyme activities solved this problem.
Nikerel
I Emrah
IE
Department of Biotechnology, TU Delft, Julianalaan 67, 2628 BC Delft, The Netherlands. i.e.nikerel@tnw.tudelft.nl
van Winden
Wouter A
WA
van Gulik
Walter M
WM
Heijnen
Joseph J
JJ
D000465:Algorithms; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D007700:Kinetics; D016014:Linear Models; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D020543:Proteome / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins; D005947:Glucose