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A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks.

ABSTRACT: The integration of various types of genomic data into predictive models of biological networks is one of the main challenges currently faced by computational biology. Constraint-based models in particular play a key role in the attempt to obtain a quantitative understanding of cellular metabolism at genome scale. In essence, their goal is to frame the metabolic capabilities of an organism based on minimal assumptions that describe the steady states of the underlying reaction network via suitable stoichiometric constraints, specifically mass balance and energy balance (i.e. thermodynamic feasibility). The implementation of these requirements to generate viable configurations of reaction fluxes and/or to test given flux profiles for thermodynamic feasibility can however prove to be computationally intensive. We propose here a fast and scalable stoichiometry-based method to explore the Gibbs energy landscape of a biochemical network at steady state. The method is applied to the problem of reconstructing the Gibbs energy landscape underlying metabolic activity in the human red blood cell, and to that of identifying and removing thermodynamically infeasible reaction cycles in the Escherichia coli metabolic network (iAF1260). In the former case, we produce consistent predictions for chemical potentials (or log-concentrations) of intracellular metabolites; in the latter, we identify a restricted set of loops (23 in total) in the periplasmic and cytoplasmic core as the origin of thermodynamic infeasibility in a large sample (10(6)) of flux configurations generated randomly and compatibly with the prior information available on reaction reversibility.

SUBMITTER: De Martino D

PROVIDER: S-EPMC3380848 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks.

De Martino Daniele D Figliuzzi Matteo M De Martino Andrea A Marinari Enzo E

PLoS computational biology 20120621 6

The integration of various types of genomic data into predictive models of biological networks is one of the main challenges currently faced by computational biology. Constraint-based models in particular play a key role in the attempt to obtain a quantitative understanding of cellular metabolism at genome scale. In essence, their goal is to frame the metabolic capabilities of an organism based on minimal assumptions that describe the steady states of the underlying reaction network via suitable ...[more]

PMID: 22737065

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Project description:BackgroundThe genomic information of a species allows for the genome-scale reconstruction of its metabolic capacity. Such a metabolic reconstruction gives support to metabolic engineering, but also to integrative bioinformatics and visualization. Sequence-based automatic reconstructions require extensive manual curation, which can be very time-consuming. Therefore, we present a method to accelerate the time-consuming process of network reconstruction for a query species. The method exploits the availability of well-curated metabolic networks and uses high-resolution predictions of gene equivalency between species, allowing the transfer of gene-reaction associations from curated networks.ResultsWe have evaluated the method using Lactococcus lactis IL1403, for which a genome-scale metabolic network was published recently. We recovered most of the gene-reaction associations (i.e. 74 - 85%) which are incorporated in the published network. Moreover, we predicted over 200 additional genes to be associated to reactions, including genes with unknown function, genes for transporters and genes with specific metabolic reactions, which are good candidates for an extension to the previously published network. In a comparison of our developed method with the well-established approach Pathologic, we predicted 186 additional genes to be associated to reactions. We also predicted a relatively high number of complete conserved protein complexes, which are derived from curated metabolic networks, illustrating the potential predictive power of our method for protein complexes.ConclusionWe show that our methodology can be applied to accelerate the reconstruction of genome-scale metabolic networks by taking optimal advantage of existing, manually curated networks. As orthology detection is the first step in the method, only the translated open reading frames (ORFs) of a newly sequenced genome are necessary to reconstruct a metabolic network. When more manually curated metabolic networks will become available in the near future, the usefulness of our method in network prediction is likely to increase.

Project description:BackgroundA central problem in computational metabolic modelling is how to find biochemically plausible pathways between metabolites in a metabolic network. Two general, complementary frameworks have been utilized to find metabolic pathways: constraint-based modelling and graph-theoretical path finding approaches. In constraint-based modelling, one aims to find pathways where metabolites are balanced in a pseudo steady-state. Constraint-based methods, such as elementary flux mode analysis, have typically a high computational cost stemming from a large number of steady-state pathways in a typical metabolic network. On the other hand, graph-theoretical approaches avoid the computational complexity of constraint-based methods by solving a simpler problem of finding shortest paths. However, while scaling well with network size, graph-theoretic methods generally tend to return more false positive pathways than constraint-based methods.ResultsIn this paper, we introduce a computational method, ReTrace, for finding biochemically relevant, branching metabolic pathways in an atom-level representation of metabolic networks. The method finds compact pathways which transfer a high fraction of atoms from source to target metabolites by considering combinations of linear shortest paths. In contrast to current steady-state pathway analysis methods, our method scales up well and is able to operate on genome-scale models. Further, we show that the pathways produced are biochemically meaningful by an example involving the biosynthesis of inosine 5'-monophosphate (IMP). In particular, the method is able to avoid typical problems associated with graph-theoretic approaches such as the need to define side metabolites or pathways not carrying any net carbon flux appearing in results. Finally, we discuss an application involving reconstruction of amino acid pathways of a recently sequenced organism demonstrating how measurement data can be easily incorporated into ReTrace analysis. ReTrace is licensed under GPL and is freely available for academic use at http://www.cs.helsinki.fi/group/sysfys/software/retrace/.ConclusionReTrace is a useful method in metabolic path finding tasks, combining some of the best aspects in constraint-based and graph-theoretic methods. It finds use in a multitude of tasks ranging from metabolic engineering to metabolic reconstruction of recently sequenced organisms.

Dataset Information

A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks.

Publications

A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks.

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