k-cone analysis: Determining all candidate values for kinetic parameters on a network scale

Iman Famili, Radhakrishnan Mahadevan, Bernhard O. Palsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

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, which 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 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 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.

Original languageEnglish
Pages (from-to)1616-1625
Number of pages10
JournalBiophysical Journal
Volume88
Issue number3
DOIs
Publication statusPublished - Mar 2005

Bibliographical note

Funding Information:
We thank the Whitaker Foundation for its support through the Graduate Fellowships in Biomedical Engineering to I.F., the National Science Foundation (BES 03-31342), and the National Institutes of Health (R01 GM68837). The authors disclose a potential financial conflict of interest.

Fingerprint

Dive into the research topics of 'k-cone analysis: Determining all candidate values for kinetic parameters on a network scale'. Together they form a unique fingerprint.

Cite this