title: DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.
abstract: Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.
authors.affiliation: INRA UR050, Laboratoire des Biotechnologies de l'Environnement, Narbonne, France; INRIA-BIOCORE, Sophia-Antipolis, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Baroukh
authors.affiliation: INRIA-BIOCORE, Sophia-Antipolis, France.
authors.forename: Rafael
authors.initials: R
authors.lastname: Muñoz-Tamayo
authors.affiliation: INRA UR050, Laboratoire des Biotechnologies de l'Environnement, Narbonne, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Steyer
authors.affiliation: INRIA-BIOCORE, Sophia-Antipolis, France; LOV-UPMC-CNRS, UMR 7093, Villefranche-sur-mer, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bernard
mesh_terms: D000465:Algorithms; D018533:Biomass; D003198:Computer Simulation; D053858:Metabolic Networks and Pathways; D058086:Microalgae / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008954:Models, Biological
references.citation: Genome Res. 2004 Feb;14(2):301-12
references.pmid: 14718379
references.citation: BMC Syst Biol. 2009 Jan 07;3:4
references.pmid: 19128495
references.citation: Bioresour Technol. 2011 Jan;102(1):142-9
references.pmid: 20656476
references.citation: Metab Eng. 2012 Jul;14(4):458-67
references.pmid: 22342232
references.citation: J Biotechnol. 2013 Apr 10;164(3):409-22
references.pmid: 22698821
references.citation: Biotechnol Bioeng. 2009 Aug 1;103(5):984-1002
references.pmid: 19449391
references.citation: PLoS Comput Biol. 2013;9(6):e1003081
references.pmid: 23843751
references.citation: BMC Syst Biol. 2011 Feb 07;5:25
references.pmid: 21294924
references.citation: Biotechnol Bioeng. 2009 Feb 1;102(2):554-68
references.pmid: 18853408
references.citation: Bioresour Technol. 2012 Sep;119:419-24
references.pmid: 22727606
references.citation: Metab Eng. 2011 Jul;13(4):401-13
references.pmid: 21315172
references.citation: J Biotechnol. 2010 Dec;150(4):497-508
references.pmid: 20869402
references.citation: Mol Syst Biol. 2009;5:271
references.pmid: 19455135
references.citation: BMC Bioinformatics. 2012 Apr 23;13:57
references.pmid: 22524245
references.citation: Science. 2010 Aug 13;329(5993):796-9
references.pmid: 20705853
references.citation: Bioinformatics. 2008 Oct 1;24(19):2229-35
references.pmid: 18676417
references.citation: J Appl Phycol. 2012 Apr;24(2):253-266
references.pmid: 22427720
references.citation: J Phycol. 2013 Apr;49(2):371-80
references.pmid: 27008523
references.citation: Metab Eng. 2013 Jan;15:25-33
references.pmid: 23022551
references.citation: Biotechnol Prog. 2011 May-Jun;27(3):631-40
references.pmid: 21567987
references.citation: Nat Rev Genet. 2004 Feb;5(2):101-13
references.pmid: 14735121
references.citation: Biophys J. 2002 Sep;83(3):1331-40
references.pmid: 12202358
references.citation: BMC Syst Biol. 2010 Apr 28;4:53
references.pmid: 20426856
references.citation: Nat Methods. 2009 Aug;6(8):589-92
references.pmid: 19597503
references.citation: J Phycol. 2012 Aug;48(4):966-75
references.pmid: 27009006
references.citation: Math Biosci. 2005 Jan;193(1):51-77
references.pmid: 15681276
references.citation: Bioresour Technol. 2011 Apr;102(8):5083-92
references.pmid: 21324679
references.citation: PLoS Comput Biol. 2012 Feb;8(2):e1002363
references.pmid: 22319433
references.citation: Bioprocess Biosyst Eng. 2005 Aug;27(5):293-301
references.pmid: 15995850
references.citation: Nat Biotechnol. 2001 Feb;19(2):125-30
references.pmid: 11175725
references.citation: Biotechnol Bioeng. 2010 Jun 1;106(2):271-84
references.pmid: 20148411
references.citation: Bioinformatics. 2002 Feb;18(2):351-61
references.pmid: 11847093
references.citation: Biotechnol Prog. 2007 Jan-Feb;23(1):83-99
references.pmid: 17269675
references.citation: Mol Syst Biol. 2011 Aug 02;7:518
references.pmid: 21811229
references.citation: Environ Sci Technol. 2013 Apr 2;47(7):3258-67
references.pmid: 23452258
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7695-700
references.pmid: 15897462
references.citation: J Biotechnol. 2007 Oct 31;132(2):134-41
references.pmid: 17658642
references.citation: J Exp Bot. 2012 Mar;63(6):2353-62
references.pmid: 22207618
references.citation: Biotechnol J. 2013 Jul;8(7):768-75
references.pmid: 23813763
references.citation: Bioprocess Biosyst Eng. 2006 Dec;29(5-6):349-66
references.pmid: 17013615
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15112-7
references.pmid: 12415116
references.citation: Curr Opin Biotechnol. 2013 Apr;24(2):300-9
references.pmid: 22981869
references.citation: BMC Genomics. 2011 Dec 22;12 Suppl 4:S5
references.pmid: 22369158
references.citation: Environ Sci Technol. 2009 Sep 1;43(17):6475-81
references.pmid: 19764204
references.citation: Trends Biotechnol. 2003 Feb;21(2):64-9
references.pmid: 12573854
references.citation: Bioresour Technol. 2011 Feb;102(3):3077-82
references.pmid: 21115343
references.citation: Plant J. 2013 Sep;75(6):1050-61
references.pmid: 23738527
references.citation: Mol Cell Biochem. 2004 Jan-Feb;256-257(1-2):5-12
references.pmid: 14977166
references.citation: Biochem Eng J. 2000 Oct 1;6(2):87-102
references.pmid: 10959082
references.citation: Nat Biotechnol. 2010 Mar;28(3):245-8
references.pmid: 20212490
references.citation: Bioresour Technol. 2011 Jan;102(1):111-7
references.pmid: 20619638
references.citation: Biotechnol Bioeng. 2003 Dec 20;84(6):647-57
references.pmid: 14595777
references.citation: Biotechnol J. 2013 Sep;8(9):1009-16
references.pmid: 23788432
references.citation: Biotechnol Adv. 2007 May-Jun;25(3):294-306
references.pmid: 17350212
references.citation: Genome Res. 2004 Nov;14(11):2367-76
references.pmid: 15520298
references.citation: Trends Biotechnol. 1999 Feb;17(2):53-60
references.pmid: 10087604