BIOPHYSICAL THEORY AND MODELING |
k-Cone Analysis: Determining All Candidate Values
for Kinetic Parameters on a Network-scale
Iman Famili 1, Radhakrishnan Mahadevan 2 and Bernhard O. Palsson 1*
1 University of California, San Diego
2 Genomatica, Inc.
* To whom correspondence should be addressed. E-mail: palsson{at}ucsd.edu.
Submitted on July 26, 2004
Revised on October 18, 2004
Accepted on 22 December 2004
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Abstract |
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The absence of comprehensive measured kinetic values and the observed inconsistency in the available in vitro kinetic data has hindered the formulation of network-scale kinetic models of biochemical reaction networks. To meet this challenge we present an approach to construct a convex space, termed the k-cone, that contains all the allowable numerical values of the kinetic constants in large-scale biochemical networks. The definition of the k-cone relies on the incorporation of in vivo concentration data and a simplified approach to represent enzyme kinetics within an established constraint-based modeling approach. The k-cone approach was implemented to define the allowable combination of numerical values for a full kinetic model of human red blood cell metabolism and to study its correlated kinetic parameters. The k-cone approach can be used to determine the consistency between in vitro measured kinetic values and in vivo concentration and flux measurements when used in a network-scale kinetic model. k-cone analysis was successful in determining whether in vitro measured kinetic values used in the reconstruction of a kinetic-based model of Saccharomyces cerevisiae central metabolism could reproduce in vivo measurements. Further, the k-cone can be used to determine which numerical values of in vitro measured parameters are required to be changed in a kinetic model if in vivo measured values are not reproduced. k-cone analysis could identify what minimum number of in vitro determined kinetic parameters needed to be adjusted in the S. cerevisiae model in order to be consistent with the in vivo data. Applying the k-cone analysis a priori to kinetic model development may reduce the time and effort involved in model building and parameter adjustment. With the recent developments in high-throughput profiling of metabolite concentrations at a whole-cell scale and advances in metabolomics technologies, the k-cone approach presented here may hold the promise for kinetic characterization of metabolic networks as well as other biological functions at a whole-cell level.
Key Words:
k-cone, constraint-based modeling approach, kinetic parameter estimation, large-scale analysis, metabolomics
