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MetaFluxNet: the management of metabolic reaction information and

quantitative metabolic flux analysis

Article  in  Bioinformatics · December 2003

DOI: 10.1093/bioinformatics/btg271 · Source: PubMed

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 Vol. 19 no. 16 2003, pages 2144–2146
BIOINFORMATICS APPLICATIONS NOTE DOI: 10.1093/bioinformatics/btg271

MetaFluxNet: the management of metabolic

reaction information and quantitative metabolic
flux analysis
Dong-Yup Lee1,2 , Hongsoek Yun2 , Sunwon Park2 and
Sang Yup Lee1,2,3, ∗
1 Metabolicand Biomolecular Engineering National Research Laboratory, 2 Department
of Chemical and Biomolecular Engineering, and BioProcess Engineering Research
Center and 3 Department of BioSystems and Bioinformatics Research Center,
Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong,
Yuseong-gu, Daejeon 305-701, Korea

Received on January 13, 2003; revised on April 24, 2003; accepted on May 9, 2003

ABSTRACT and Fluxmap (http://www.biotecnol.com/Paginas/Fluxmap.

Summary: MetaFluxNet is a program package for man- htm). However, most of the programs available have focused

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aging information on the metabolic reaction network and for on the limited part of MFA. Moreover, to our knowledge
quantitatively analyzing metabolic fluxes in an interactive and there is no MFA tool supporting dynamic visualization of
customized way. It allows users to interpret and examine meta- calculated fluxes mapped on metabolic pathways. Here, we
bolic behavior in response to genetic and/or environmental have developed an integrated program package MetaFluxNet
modifications. As a result, quantitative in silico simulations of satisfying various computational demands in the flux
metabolic pathways can be carried out to understand the meta- analysis.
bolic status and to design the metabolic engineering strategies.
The main features of the program include a well-developed
model construction environment, user-friendly interface for PROGRAM OVERVIEW
metabolic flux analysis (MFA), comparative MFA of strains MetaFluxNet (version 1.6) provides with an easy and
having different genotypes under various environmental con- customized environment for constructing a metabolic reac-
ditions, and automated pathway layout creation. tion network and for performing MFA and dynamic visu-
Availability: http://mbel.kaist.ac.kr/ alization of the MFA results. The package was mainly
Contact: [email protected] written in Microsoft’s programming language C# under
Supplementary information: A manual for MetaFluxNet is the .NET platform, where several Java libraries for the
available as PDF file. graph layout in dynamic visualization and computational
algorithms in MFA are all integrated: JAMA package
INTRODUCTION (http://math.nist.gov/javanumerics/jama/) for various matrix
Analysis and modeling of the metabolic network are essen- operations; lp_solve (http://www.cs.wustl.edu/∼javagrp/help/
tial in understanding complex biological functions. Sev- LinearProgramming.html) for simplex algorithm of linear
eral available approaches for such analysis and modeling programming (LP); VGJ (ftp://ftp.eng.auburn.edu/pub/
include structural pathway analysis, metabolic flux analysis larrybar/VGJ.zip) for the graph layout. The main features of
(MFA), metabolic control analysis and dynamic simulation the MetaFluxNet are as follows.
(Stephanopoulos et al., 1998). Among them, MFA is most
widely adopted for rational design and in silico engineering of Construction of a metabolic reaction model
metabolic pathways based on the stoichiometry of metabolic MetaFluxNet provides users with a well-developed model
reactions and mass balances around the metabolites under construction environment. It allows users to set up their own
steady-state assumption (Lee and Papoutsakis, 1999). metabolic reaction network models by registering information
Several computer programs have been developed to assist on two object classes, Metabolites and Reactions, which are
users in implementing MFA easily: FBA (http://gcrg.ucsd.edu/ interactively linked in a metabolic system. Each class con-
downloads/index.html), FluxAnalyzer (Klamt et al., 2003), sists of several fields describing biological information. For
example, the entries of the Reactions class contain Enzyme
∗ To whom correspondence should be addressed. Commission (EC) number, gene name, and substrates and

2144 Bioinformatics 19(16) © Oxford University Press 2003; all rights reserved.
 MetaFluxNet

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Fig. 1. Screen shot of the flux analysis part of MetaFluxNet. Flux distributions can be interactively determined and dynamically visualized
via user-friendly interface.

products participating in the reaction. Data contents in the Comparative flux analysis
fields can be edited, stored and modified individually by MetaFluxNet also allows the users to investigate the influ-
the users. ences of gene addition or deletion, and of varying cultivation
conditions on the optimal metabolic flux distribution. This
makes it possible to understand the metabolic and physiolo-
Metabolic flux analysis gical changes of cell under different conditions, and con-
MetaFluxNet provides a user-friendly interface for MFA as sequently to design new metabolic engineering strategies to
shown in Figure 1. Once the metabolic reaction model is achieve desired goals. Furthermore, the results of compar-
constructed, a stoichiometric model is defined under the ative MFA are displayed in one window, where specified
steady-state assumption on the basis of measured reaction measurements and gene modification (addition or deletion)
rates or fluxes. Then, the defined system is classified by can be represented by ‘measured’ and ‘added or deleted’,
one of four possible cases according to Determinacy and respectively, in the state field of fluxes, while the states of non-
Redundancy (Klamt et al., 2002). In the case of the determ- measured metabolic fluxes are categorized by ‘calculated’ and
ined system, a unique solution or a least-squares solution is ‘bound’. Using this feature of MetaFluxNet, one can design
obtained by matrix operations if the system is observable. and evaluate various metabolically engineered in silico strains
Otherwise, measured fluxes are reconciled to remove the by relaxing the capacity range of bound fluxes and/or by
inconsistency in the case of the redundant system, followed by changing the genotypes.
inspecting calculable fluxes which can be uniquely determined
by the least-squares solution using the pseudo-inverse (see
Klamt et al., 2002). LP approach can be exploited to quantify Visualization of reaction pathways and flux
optimal flux distribution by optimizing a desired physiological distribution
property (objective function) such as growth rate, substrate MetaFluxNet provides an interactive and dynamic graphical
uptake rate and product formation rate (Stephanopoulos et al., user interface to display metabolic reaction pathways with
1998). flux distribution results as shown in Figure 1. The pathways

2145
D.-Y.Lee et al.

are automatically and dynamically visualized by the spring REFERENCES

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This work was supported by the National Research Laboratory Lee,S.Y. and Papoutsakis,E.T. (eds.) (1999) Metabolic Engineering.
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