Metabolomics integrated elementary flux mode analysis in large metabolic networks

Scientific Reports
Matthias P GerstlJürgen Zanghellini

Abstract

Elementary flux modes (EFMs) are non-decomposable steady-state pathways in metabolic networks. They characterize phenotypes, quantify robustness or identify engineering targets. An EFM analysis (EFMA) is currently restricted to medium-scale models, as the number of EFMs explodes with the network's size. However, many topologically feasible EFMs are biologically irrelevant. We present thermodynamic EFMA (tEFMA), which calculates only the small(er) subset of thermodynamically feasible EFMs. We integrate network embedded thermodynamics into EFMA and show that we can use the metabolome to identify and remove thermodynamically infeasible EFMs during an EFMA without losing biologically relevant EFMs. Calculating only the thermodynamically feasible EFMs strongly reduces memory consumption and program runtime, allowing the analysis of larger networks. We apply tEFMA to study the central carbon metabolism of E. coli and find that up to 80% of its EFMs are thermodynamically infeasible. Moreover, we identify glutamate dehydrogenase as a bottleneck, when E. coli is grown on glucose and explain its inactivity as a consequence of network embedded thermodynamics. We implemented tEFMA as a Java package which is available for download at https:...Continue Reading

References

Aug 29, 1998·Journal of Bacteriology·R B Helling
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S Edwards, B O Palsson
May 15, 2002·The Journal of Biological Chemistry·Markus W Covert, Bernhard Ø Palsson
Sep 21, 2002·Molecular Biology Reports·Steffen Klamt, Jörg Stelling
Sep 4, 2003·Genome Biology·Jennifer L ReedBernhard O Palsson
Nov 6, 2004·BMC Bioinformatics·Julien Gagneur, Steffen Klamt
Apr 6, 2006·BMC Bioinformatics·Jean-Marc Schwartz, Minoru Kanehisa
Jun 22, 2006·Molecular Systems Biology·Anne KümmelMatthias Heinemann
Dec 19, 2006·Biophysical Journal·Christopher S HenryVassily Hatzimanikatis
Aug 5, 2008·Bioinformatics·Marco Terzer, Jörg Stelling
Aug 30, 2008·Bio Systems·Vicente AcuñaLeen Stougie
Jun 30, 2009·Nature Chemical Biology·Bryson D BennettJoshua D Rabinowitz
Oct 2, 2009·Bioinformatics·Luis F de FigueiredoFrancisco J Planes
Nov 6, 2009·Molecular Systems Biology·Matthew A OberhardtJason A Papin
Mar 10, 2010·Nature Biotechnology·Jeffrey D OrthBernhard Ø Palsson
May 28, 2010·Biotechnology and Bioengineering·Vidya V IyerCharles M Roth
Sep 14, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Erwin P GianchandaniJason A Papin
Nov 18, 2010·Biophysical Journal·Stefan J JolMatthias Heinemann
Mar 18, 2011·Omics : a Journal of Integrative Biology·Hong YangMarianthi G Ierapetritou
Aug 19, 2011·Biotechnology Advances·Tobias OsterlundJens Nielsen
Nov 9, 2011·Nucleic Acids Research·Avi FlamholzRon Milo
Mar 1, 2012·Nature Reviews. Microbiology·Nathan E LewisBernhard O Palsson
Mar 15, 2012·PLoS Computational Biology·Stefan J JolMatthias Heinemann
Aug 17, 2012·Scientific Reports·Steven M KelkFrank J Bruggeman
Sep 11, 2012·Bioinformatics·Daniel MachadoIsabel Rocha
Jun 8, 2013·Bioinformatics·Alberto RezolaFrancisco J Planes
Jun 22, 2013·Biotechnology Journal·Jürgen ZanghelliniChristian Jungreuthmayer
Jul 23, 2013·PLoS Computational Biology·Elad NoorRonan M T Fleming
Feb 24, 2015·Bioinformatics·Matthias P GerstlJürgen Zanghellini

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Citations

Dec 20, 2015·Bioinformatics·Jan Bert van Klinken, Ko Willems van Dijk
Dec 26, 2015·Metabolic Engineering·Lisa Maria DerschChristoph Wittmann
Nov 7, 2015·Bioinformatics·Matthias P GerstlJürgen Zanghellini
Mar 5, 2016·The FEBS Journal·Matthias P GerstlJürgen Zanghellini
Dec 13, 2016·Metabolites·Verónica S Martínez, Jens O Krömer
Feb 22, 2017·PloS One·Sabine PeresStefan Schuster
Feb 17, 2018·PLoS Computational Biology·Meike T WortelWolfram Liebermeister
Jun 15, 2018·International Journal of Molecular Sciences·Fidele TugizimanaIan A Dubery
May 11, 2018·Biochemical Society Transactions·Sabine PeresPhilippe Dague
Feb 24, 2015·Bioinformatics·Matthias P GerstlJürgen Zanghellini
Jul 30, 2020·Metabolites·Svetlana VolkovaIgor Marín de Mas
Jan 17, 2019·Bioinformatics·Matthias P GerstlJürgen Zanghellini
Dec 5, 2020·PloS One·Marcelo Rivas-Astroza, Raúl Conejeros

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Software Mentioned

NET
eQuilibrator
efmtool
tEFMA )
tEFMA
thermodynamic EFMA (
CPLEX
EFMA

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