{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:10:15Z","timestamp":1778220615011,"version":"3.51.4"},"reference-count":119,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:00:00Z","timestamp":1692835200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>In microorganisms, different from primary metabolism for cellular growth, secondary metabolism is for ecological interactions and stress responses and an important source of natural products widely used in various areas such as pharmaceutics and food additives. With advancements of sequencing technologies and bioinformatics tools, a large number of biosynthetic gene clusters of secondary metabolites have been discovered from microbial genomes. However, due to challenges from the difficulty of genome-scale pathway reconstruction and the limitation of conventional flux balance analysis (FBA) on secondary metabolism, the quantitative modeling of secondary metabolism is poorly established, in contrast to that of primary metabolism. This review first discusses current efforts on the reconstruction of secondary metabolic pathways in genome-scale metabolic models (GSMMs), as well as related FBA-based modeling techniques. Additionally, potential extensions of FBA are suggested to improve the prediction accuracy of secondary metabolite production. As this review posits, biosynthetic pathway reconstruction for various secondary metabolites will become automated and a modeling framework capturing secondary metabolism onset will enhance the predictive power. Expectedly, an improved FBA-based modeling workflow will facilitate quantitative study of secondary metabolism and in silico design of engineering strategies for natural product production.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011391","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T17:23:00Z","timestamp":1692897780000},"page":"e1011391","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":36,"title":["Flux balance analysis-based metabolic modeling of microbial secondary metabolism: Current status and outlook"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1936-1223","authenticated-orcid":true,"given":"Sizhe","family":"Qiu","sequence":"first","affiliation":[]},{"given":"Aidong","family":"Yang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-4466","authenticated-orcid":true,"given":"Hong","family":"Zeng","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"pcbi.1011391.ref001","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s10295-019-02136-y","article-title":"Toward a global picture of bacterial secondary metabolism","volume":"46","author":"MR Seyedsayamdost","year":"2019","journal-title":"J Ind Microbiol Biotechnol"},{"key":"pcbi.1011391.ref002","volume-title":"Secondary Metabolism","author":"J. Mann","year":"1987"},{"key":"pcbi.1011391.ref003","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/B978-0-12-809633-8.21072-8","article-title":"The Biosynthesis of Fungal Secondary Metabolites: From Fundamentals to Biotechnological Applications.","author":"O Mosunova","year":"2021","journal-title":"Encyclopedia of Mycology."},{"key":"pcbi.1011391.ref004","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.79766","article-title":"An Introductory Chapter: Secondary Metabolites.","author":"D Thirumurugan","year":"2018","journal-title":"Secondary Metabolites\u2014Sources and Applications."},{"key":"pcbi.1011391.ref005","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/B978-0-12-811372-1.00003-8","article-title":"Microbial Biosynthesis: A Repertory of Vital Natural Products.","author":"SM Abdel-Aziz","year":"2017","journal-title":"Food Biosynthesis."},{"key":"pcbi.1011391.ref006","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.copbio.2011.03.010","article-title":"An ecological perspective of microbial secondary metabolism","volume":"22","author":"J O\u2019Brien","year":"2011","journal-title":"Curr Opin Biotechnol"},{"key":"pcbi.1011391.ref007","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s10295-013-1387-y","article-title":"Activating secondary metabolism with stress and chemicals","volume":"41","author":"V Yoon","year":"2014","journal-title":"J Ind Microbiol Biotechnol"},{"key":"pcbi.1011391.ref008","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1128\/AEM.64.3.843-849.1998","article-title":"Regulation of the Aspergillus nidulans penicillin biosynthesis gene acvA (pcbAB) by amino acids: implication for involvement of transcription factor PACC.","volume":"64","author":"K Then Bergh","year":"1998","journal-title":"Appl Environ Microbiol"},{"key":"pcbi.1011391.ref009","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1073\/pnas.1316283111","article-title":"Private link between signal and response in Bacillus subtilis quorum sensing","volume":"111","author":"A Oslizlo","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011391.ref010","first-page":"65","article-title":"Microbial Natural Products. Natural Products","author":"S Sanchez","year":"2012","journal-title":"Chem Biol"},{"key":"pcbi.1011391.ref011","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1021\/acs.jnatprod.9b00110","article-title":"Bioactive Secondary Metabolites from Bacillus subtilis: A Comprehensive Review","volume":"82","author":"F Kaspar","year":"2019","journal-title":"J Nat Prod"},{"key":"pcbi.1011391.ref012","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.tifs.2021.02.014","article-title":"Exopolysaccharides from lactic acid bacteria: Techno-functional application in the food industry","volume":"110","author":"E Korcz","year":"2021","journal-title":"Trends Food Sci Technol"},{"key":"pcbi.1011391.ref013","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1080\/09670262.2016.1214882","article-title":"Cyanobacterial metabolites as a source of sunscreens and moisturizers: a comparison with current synthetic compounds","volume":"52","author":"P Derikvand","year":"2017","journal-title":"Eur J Phycol"},{"key":"pcbi.1011391.ref014","doi-asserted-by":"crossref","first-page":"20180789","DOI":"10.1098\/rspb.2018.0789","article-title":"The distribution of bacterial doubling times in the wild","volume":"285","author":"B Gibson","year":"2018","journal-title":"Proc R Soc B Biol Sci"},{"key":"pcbi.1011391.ref015","article-title":"Plant cell biotechnology","author":"D. Brownleader","journal-title":"Plant Biochem"},{"key":"pcbi.1011391.ref016","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1080\/10408398.2019.1575791","article-title":"Current status of biotechnological production and applications of microbial exopolysaccharides.","volume":"60","author":"MCS Barcelos","year":"2020","journal-title":"Crit Rev Food Sci Nutr"},{"key":"pcbi.1011391.ref017","article-title":"A Review of the Microbial Production of Bioactive Natural Products and Biologics.","volume":"10","author":"JV Pham","year":"2019","journal-title":"Front Microbiol."},{"key":"pcbi.1011391.ref018","doi-asserted-by":"crossref","first-page":"102762","DOI":"10.1016\/j.copbio.2022.102762","article-title":"Biotechnological application of Streptomyces for the production of clinical drugs and other bioactive molecules","volume":"77","author":"F Del Carratore","year":"2022","journal-title":"Curr Opin Biotechnol"},{"key":"pcbi.1011391.ref019","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1021\/sb4000228","article-title":"Modeling challenges in the synthetic biology of secondary metabolism","volume":"2","author":"R Breitling","year":"2013","journal-title":"ACS Synth Biol"},{"key":"pcbi.1011391.ref020","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.mib.2018.03.004","article-title":"Omics and multi-omics approaches to study the biosynthesis of secondary metabolites in microorganisms","volume":"45","author":"E Palazzotto","year":"2018","journal-title":"Curr Opin Microbiol"},{"key":"pcbi.1011391.ref021","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.synbio.2015.12.002","article-title":"The secondary metabolite bioinformatics portal: Computational tools to facilitate synthetic biology of secondary metabolite production","volume":"1","author":"T Weber","year":"2016","journal-title":"Synth Syst Biotechnol"},{"key":"pcbi.1011391.ref022","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jbiotec.2015.12.023","article-title":"Kinetic modeling of cell metabolism for microbial production","volume":"219","author":"RS Costa","year":"2016","journal-title":"J Biotechnol"},{"key":"pcbi.1011391.ref023","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.copbio.2020.11.010","article-title":"Building kinetic models for metabolic engineering","volume":"67","author":"CJ Foster","year":"2021","journal-title":"Curr Opin Biotechnol"},{"key":"pcbi.1011391.ref024","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nbt.1614","article-title":"What is flux balance analysis?","volume":"28","author":"JD Orth","year":"2010","journal-title":"Nat Biotechnol"},{"key":"pcbi.1011391.ref025","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/00986449008940684","article-title":"ADAPTIVE CONTROL OF FEDBATCH BIOREACTORS","volume":"87","author":"D Dochain","year":"1990","journal-title":"Chem Eng Commun"},{"key":"pcbi.1011391.ref026","article-title":"Unstructured models for lactic acid fermentation-a review","author":"A Bouguettoucha","year":"2011","journal-title":"Food Technol"},{"key":"pcbi.1011391.ref027","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.cels.2017.11.013","article-title":"Metabolic Models of Protein Allocation Call for the Kinetome","volume":"5","author":"A Nilsson","year":"2017","journal-title":"Cell Syst"},{"key":"pcbi.1011391.ref028","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00239-015-9681-0","article-title":"Evolution of Enzyme Kinetic Mechanisms","volume":"80","author":"NN Ulusu","year":"2015","journal-title":"J Mol Evol"},{"key":"pcbi.1011391.ref029","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1042\/BST20170246","article-title":"Methods for automated genome-scale metabolic model reconstruction","volume":"46","author":"JP Faria","year":"2018","journal-title":"Biochem Soc Trans"},{"key":"pcbi.1011391.ref030","doi-asserted-by":"crossref","first-page":"i311","DOI":"10.1093\/bioinformatics\/btx251","article-title":"popFBA: tackling intratumour heterogeneity with Flux Balance Analysis","volume":"33","author":"C Damiani","year":"2017","journal-title":"Bioinformatics"},{"key":"pcbi.1011391.ref031","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1073\/pnas.0813229106","article-title":"Identifying essential genes in Escherichia coli from a metabolic optimization principle","volume":"106","author":"C Martelli","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011391.ref032","doi-asserted-by":"crossref","first-page":"e1800377","DOI":"10.1002\/biot.201800377","article-title":"Genome-Scale Metabolic Reconstruction of Actinomycetes for Antibiotics Production.","volume":"14","author":"OS Mohite","year":"2019","journal-title":"Biotechnol J."},{"key":"pcbi.1011391.ref033","doi-asserted-by":"crossref","first-page":"W339","DOI":"10.1093\/nar\/gkr466","article-title":"antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences","volume":"39","author":"MH Medema","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref034","doi-asserted-by":"crossref","first-page":"W49","DOI":"10.1093\/nar\/gkx320","article-title":"PRISM 3: expanded prediction of natural product chemical structures from microbial genomes","volume":"45","author":"MA Skinnider","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref035","doi-asserted-by":"crossref","first-page":"W273","DOI":"10.1093\/nar\/gkl237","article-title":"BAGEL: a web-based bacteriocin genome mining tool","volume":"34","author":"A de Jong","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref036","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nchembio.1884","article-title":"Computational approaches to natural product discovery","volume":"11","author":"MH Medema","year":"2015","journal-title":"Nat Chem Biol"},{"key":"pcbi.1011391.ref037","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1039\/C6NP00025H","article-title":"The evolution of genome mining in microbes\u2013a review","volume":"33","author":"N Ziemert","year":"2016","journal-title":"Nat Prod Rep"},{"key":"pcbi.1011391.ref038","first-page":"141","volume-title":"In Silico Approach for Sustainable Agriculture.","author":"M Tania, Goyal","year":"2018"},{"key":"pcbi.1011391.ref039","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1093\/bib\/bbx020","article-title":"Bioinformatics tools for the identification of gene clusters that biosynthesize specialized metabolites","volume":"19","author":"AK Chavali","year":"2018","journal-title":"Brief Bioinform"},{"key":"pcbi.1011391.ref040","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1093\/bib\/bbx146","article-title":"Recent development of antiSMASH and other computational approaches to mine secondary metabolite biosynthetic gene clusters","volume":"20","author":"K Blin","year":"2019","journal-title":"Brief Bioinform"},{"key":"pcbi.1011391.ref041","doi-asserted-by":"crossref","first-page":"100795","DOI":"10.1016\/j.isci.2019.100795","article-title":"Computational Tools for Discovering and Engineering Natural Product Biosynthetic Pathways.","volume":"23","author":"H Ren","year":"2020","journal-title":"iScience"},{"key":"pcbi.1011391.ref042","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12859-021-03985-0","article-title":"Automatic reconstruction of metabolic pathways from identified biosynthetic gene clusters","volume":"22","author":"S Sulheim","year":"2021","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1011391.ref043","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.synbio.2017.11.002","article-title":"A review of computational tools for design and reconstruction of metabolic pathways.","volume":"2","author":"L Wang","year":"2017","journal-title":"Synth Syst Biotechnol"},{"key":"pcbi.1011391.ref044","doi-asserted-by":"crossref","first-page":"7542","DOI":"10.1093\/nar\/gky537","article-title":"Fast automated reconstruction of genome-scale metabolic models for microbial species and communities","volume":"46","author":"D Machado","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref045","doi-asserted-by":"crossref","first-page":"D575","DOI":"10.1093\/nar\/gkaa746","article-title":"The ModelSEED Biochemistry Database for the integration of metabolic annotations and the reconstruction, comparison and analysis of metabolic models for plants, fungi and microbes","volume":"49","author":"SMD Seaver","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref046","doi-asserted-by":"crossref","first-page":"e1006541","DOI":"10.1371\/journal.pcbi.1006541","article-title":"RAVEN 2.0: A versatile toolbox for metabolic network reconstruction and a case study on Streptomyces coelicolor.","volume":"14","author":"H Wang","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011391.ref047","article-title":"merlin v4.0: an updated platform for the reconstruction of high-quality genome-scale metabolic models.","volume":"2021","author":"J Capela","year":"2021","journal-title":"bioRxiv."},{"key":"pcbi.1011391.ref048","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1186\/s12859-018-2472-z","article-title":"Automated generation of genome-scale metabolic draft reconstructions based on KEGG","volume":"19","author":"E Karlsen","year":"2018","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1011391.ref049","doi-asserted-by":"crossref","first-page":"e1006146","DOI":"10.1371\/journal.pcbi.1006146","article-title":"Traceability, reproducibility and wiki-exploration for \u2018\u00e0-la-carte\u2019 reconstructions of genome-scale metabolic models.","volume":"14","author":"M Aite","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011391.ref050","author":"B. Olivier","year":"2018","journal-title":"SystemsBioinformatics\/cbmpy-metadraft: MetaDraft is now available"},{"key":"pcbi.1011391.ref051","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/bib\/bbz104","article-title":"Pathway Tools version 23.0 update: software for pathway\/genome informatics and systems biology","volume":"22","author":"PD Karp","year":"2019","journal-title":"Brief Bioinform"},{"key":"pcbi.1011391.ref052","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1752-0509-6-8","article-title":"FAME, the Flux Analysis and Modeling Environment","volume":"6","author":"J Boele","year":"2012","journal-title":"BMC Syst Biol"},{"key":"pcbi.1011391.ref053","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1093\/bioinformatics\/bts267","article-title":"GEMSiRV: a software platform for GEnome-scale metabolic model simulation, reconstruction and visualization","volume":"28","author":"Y-C Liao","year":"2012","journal-title":"Bioinformatics"},{"key":"pcbi.1011391.ref054","first-page":"D402","article-title":"BiGG Models 2020: multi-strain genome-scale models and expansion across the phylogenetic tree","volume":"48","author":"CJ Norsigian","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref055","doi-asserted-by":"crossref","first-page":"D633","DOI":"10.1093\/nar\/gkx935","article-title":"The MetaCyc database of metabolic pathways and enzymes","volume":"46","author":"R Caspi","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref056","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"M Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref057","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1002\/bit.26739","article-title":"Reconstruction of 24 Penicillium genome-scale metabolic models shows diversity based on their secondary metabolism","volume":"115","author":"S Prigent","year":"2018","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref058","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1104\/pp.105.060376","article-title":"MetaCyc and AraCyc. Metabolic pathway databases for plant research","volume":"138","author":"P Zhang","year":"2005","journal-title":"Plant Physiol"},{"key":"pcbi.1011391.ref059","doi-asserted-by":"crossref","first-page":"D445","DOI":"10.1093\/nar\/gkz862","article-title":"The MetaCyc database of metabolic pathways and enzymes\u2014a 2019 update","volume":"48","author":"R Caspi","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref060","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1471-2105-14-112","article-title":"A systematic comparison of the MetaCyc and KEGG pathway databases","volume":"14","author":"T Altman","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1011391.ref061","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nbt.2870","article-title":"Optimizing genome-scale network reconstructions","volume":"32","author":"J Monk","year":"2014","journal-title":"Nat Biotechnol"},{"key":"pcbi.1011391.ref062","doi-asserted-by":"crossref","DOI":"10.3390\/metabo11050304","article-title":"Reconstruction of a Genome-Scale Metabolic Model of Streptomyces albus J1074: Improved Engineering Strategies in Natural Product Synthesis.","volume":"11","author":"C Kittikunapong","year":"2021","journal-title":"Metabolites"},{"key":"pcbi.1011391.ref063","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.gene.2014.10.034","article-title":"Reconstruction and analysis of the genome-scale metabolic model of Lactobacillus casei LC2W","volume":"554","author":"N Xu","year":"2015","journal-title":"Gene"},{"key":"pcbi.1011391.ref064","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1016\/j.febslet.2012.02.008","article-title":"Metabolomics methods for the synthetic biology of secondary metabolism","volume":"586","author":"Q-T Nguyen","year":"2012","journal-title":"FEBS Lett"},{"key":"pcbi.1011391.ref065","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1093\/bioinformatics\/btz677","article-title":"DDAP: docking domain affinity and biosynthetic pathway prediction tool for type I polyketide synthases","volume":"36","author":"T Li","year":"2020","journal-title":"Bioinformatics"},{"key":"pcbi.1011391.ref066","doi-asserted-by":"crossref","first-page":"101525","DOI":"10.1016\/j.isci.2020.101525","article-title":"Enzyme-Constrained Models and Omics Analysis of Streptomyces coelicolor Reveal Metabolic Changes that Enhance Heterologous Production","volume":"23","author":"S Sulheim","year":"2020","journal-title":"iScience"},{"key":"pcbi.1011391.ref067","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ymben.2017.12.002","article-title":"RetroPath2.0: A retrosynthesis workflow for metabolic engineers","volume":"45","author":"B Del\u00e9pine","year":"2018","journal-title":"Metab Eng"},{"key":"pcbi.1011391.ref068","article-title":"BioNavi-NP: Biosynthesis Navigator for Natural Products.","author":"S Zheng","year":"2021","journal-title":"arXiv [q-bio.QM]."},{"key":"pcbi.1011391.ref069","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nchembio.580","article-title":"Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol.","volume":"7","author":"H Yim","year":"2011","journal-title":"Nat Chem Biol."},{"key":"pcbi.1011391.ref070","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1021\/acssynbio.6b00054","article-title":"ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies.","volume":"5","author":"N Hadadi","year":"2016","journal-title":"ACS Synth Biol"},{"key":"pcbi.1011391.ref071","first-page":"1","article-title":"A retrosynthetic analysis algorithm implementation.","volume":"11","author":"IA Watson","year":"2019","journal-title":"J Chem"},{"key":"pcbi.1011391.ref072","doi-asserted-by":"crossref","DOI":"10.3390\/microorganisms9112352","article-title":"Genome-Scale Reconstruction of Microbial Dynamic Phenotype: Successes and Challenges.","volume":"9","author":"NS Panikov","year":"2021","journal-title":"Microorganisms"},{"key":"pcbi.1011391.ref073","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nprot.2007.99","article-title":"Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox","volume":"2","author":"SA Becker","year":"2007","journal-title":"Nat Protoc"},{"key":"pcbi.1011391.ref074","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-1-0716-1585-0_12","article-title":"Metabolic Modeling with MetaFlux.","volume":"2349","author":"M Latendresse","year":"2022","journal-title":"Methods Mol Biol"},{"key":"pcbi.1011391.ref075","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1093\/bioinformatics\/btp408","article-title":"FBA-SimVis: interactive visualization of constraint-based metabolic models","volume":"25","author":"E Grafahrend-Belau","year":"2009","journal-title":"Bioinformatics"},{"key":"pcbi.1011391.ref076","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ymben.2010.11.004","article-title":"Synergy between 13C-metabolic flux analysis and flux balance analysis for understanding metabolic adaption to anaerobiosis in E. coli","volume":"13","author":"X Chen","year":"2011","journal-title":"Metab Eng"},{"key":"pcbi.1011391.ref077","doi-asserted-by":"crossref","first-page":"101818","DOI":"10.1016\/j.isci.2020.101818","article-title":"A Hybrid Flux Balance Analysis and Machine Learning Pipeline Elucidates Metabolic Adaptation in Cyanobacteria.","volume":"23","author":"S Vijayakumar","year":"2020","journal-title":"iScience"},{"key":"pcbi.1011391.ref078","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/bit.10803","article-title":"Optknock: a bilevel programming framework for identifying gene knockout strategies for microbial strain optimization","volume":"84","author":"AP Burgard","year":"2003","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref079","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1093\/nar\/gkab815","article-title":"metaGEM: reconstruction of genome scale metabolic models directly from metagenomes","volume":"49","author":"F Zorrilla","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011391.ref080","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.biotechadv.2013.05.002","article-title":"Flux analysis and metabolomics for systematic metabolic engineering of microorganisms","volume":"31","author":"Y Toya","year":"2013","journal-title":"Biotechnol Adv"},{"key":"pcbi.1011391.ref081","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1471-2164-11-10","article-title":"The dynamic architecture of the metabolic switch in Streptomyces coelicolor","volume":"11","author":"K Nieselt","year":"2010","journal-title":"BMC Genomics"},{"key":"pcbi.1011391.ref082","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1534\/g3.116.033084","article-title":"Regulation of Secondary Metabolism by the Velvet Complex Is Temperature-Responsive in Aspergillus","volume":"6","author":"AL Lind","year":"2016","journal-title":"G3"},{"key":"pcbi.1011391.ref083","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrmicro2916","article-title":"Regulation of fungal secondary metabolism","volume":"11","author":"AA Brakhage","year":"2013","journal-title":"Nat Rev Microbiol"},{"key":"pcbi.1011391.ref084","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1751-7915.2010.00235.x","article-title":"Cross-talk of global nutritional regulators in the control of primary and secondary metabolism in Streptomyces.","volume":"4","author":"JF Mart\u00edn","year":"2011","journal-title":"J Microbial Biotechnol"},{"key":"pcbi.1011391.ref085","article-title":"Carbon source regulation of idiolite biosynthesis in actinomycetes","author":"AL Demain","journal-title":"Regulation of secondary metabolism in Actinomycetes"},{"key":"pcbi.1011391.ref086","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/btpr.1949","article-title":"Comparison and analysis of objective functions in flux balance analysis","volume":"30","author":"CE Garc\u00eda S\u00e1nchez","year":"2014","journal-title":"Biotechnol Prog"},{"key":"pcbi.1011391.ref087","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/1471-2164-11-202","article-title":"Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor","volume":"11","author":"MT Alam","year":"2010","journal-title":"BMC Genomics"},{"key":"pcbi.1011391.ref088","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1186\/s12864-018-4905-5","article-title":"Development and validation of an updated computational model of Streptomyces coelicolor primary and secondary metabolism","volume":"19","author":"A Amara","year":"2018","journal-title":"BMC Genomics"},{"key":"pcbi.1011391.ref089","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00449-018-1900-9","article-title":"An enhanced genome-scale metabolic reconstruction of Streptomyces clavuligerus identifies novel strain improvement strategies.","volume":"41","author":"L Toro","year":"2018","journal-title":"Bioprocess Biosyst Eng"},{"key":"pcbi.1011391.ref090","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/bit.25167","article-title":"Genome scale metabolic modeling of the riboflavin overproducer Ashbya gossypii","volume":"111","author":"R Ledesma-Amaro","year":"2014","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref091","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1046\/j.1462-2920.2001.00225.x","article-title":"Riboflavin, overproduced during sporulation of Ashbya gossypii, protects its hyaline spores against ultraviolet light","volume":"3","author":"KP Stahmann","year":"2001","journal-title":"Environ Microbiol"},{"key":"pcbi.1011391.ref092","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/bit.27565","article-title":"Dynamic co-culture metabolic models reveal the fermentation dynamics, metabolic capacities and interplays of cheese starter cultures","volume":"118","author":"E \u00d6zcan","year":"2021","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref093","doi-asserted-by":"crossref","first-page":"e1000082","DOI":"10.1371\/journal.pcbi.1000082","article-title":"Context-specific metabolic networks are consistent with experiments.","volume":"4","author":"SA Becker","year":"2008","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011391.ref094","doi-asserted-by":"crossref","first-page":"e1000489","DOI":"10.1371\/journal.pcbi.1000489","article-title":"Interpreting expression data with metabolic flux models: predicting Mycobacterium tuberculosis mycolic acid production","volume":"5","author":"C Colijn","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011391.ref095","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1093\/bioinformatics\/btq602","article-title":"iMAT: an integrative metabolic analysis tool","volume":"26","author":"H Zur","year":"2010","journal-title":"Bioinformatics"},{"key":"pcbi.1011391.ref096","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.csbj.2014.08.009","article-title":"Methods for integration of transcriptomic data in genome-scale metabolic models.","volume":"11","author":"MK Kim","year":"2014","journal-title":"Comput Struct Biotechnol J"},{"key":"pcbi.1011391.ref097","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1002\/bit.25830","article-title":"Transcriptomics-based strain optimization tool for designing secondary metabolite overproducing strains of Streptomyces coelicolor","volume":"113","author":"M Kim","year":"2016","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref098","doi-asserted-by":"crossref","first-page":"935","DOI":"10.15252\/msb.20167411","article-title":"Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints","volume":"13","author":"BJ S\u00e1nchez","year":"2017","journal-title":"Mol Syst Biol"},{"key":"pcbi.1011391.ref099","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1126\/science.1192588","article-title":"Interdependence of cell growth and gene expression: origins and consequences","volume":"330","author":"M Scott","year":"2010","journal-title":"Science"},{"key":"pcbi.1011391.ref100","doi-asserted-by":"crossref","first-page":"784","DOI":"10.15252\/msb.20145697","article-title":"Quantitative proteomic analysis reveals a simple strategy of global resource allocation in bacteria","volume":"11","author":"S Hui","year":"2015","journal-title":"Mol Syst Biol"},{"key":"pcbi.1011391.ref101","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1186\/s12859-021-04382-3","article-title":"Understanding and mathematical modelling of cellular resource allocation in microorganisms: a comparative synthesis","volume":"22","author":"H Zeng","year":"2021","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1011391.ref102","doi-asserted-by":"crossref","first-page":"e1004913","DOI":"10.1371\/journal.pcbi.1004913","article-title":"Constrained Allocation Flux Balance Analysis.","volume":"12","author":"M Mori","year":"2016","journal-title":"PLoS Comput Biol."},{"key":"pcbi.1011391.ref103","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.mib.2018.01.002","article-title":"Modeling the multi-scale mechanisms of macromolecular resource allocation","volume":"45","author":"L Yang","year":"2018","journal-title":"Curr Opin Microbiol"},{"key":"pcbi.1011391.ref104","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature15765","article-title":"Overflow metabolism in Escherichia coli results from efficient proteome allocation","volume":"528","author":"M Basan","year":"2015","journal-title":"Nature"},{"key":"pcbi.1011391.ref105","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12918-018-0677-4","article-title":"Modelling overflow metabolism in Escherichia coli with flux balance analysis incorporating differential proteomic efficiencies of energy pathways","volume":"13","author":"H Zeng","year":"2019","journal-title":"BMC Syst Biol"},{"key":"pcbi.1011391.ref106","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1002\/bit.27605","article-title":"Resource allocation explains lactic acid production in mixed-culture anaerobic fermentations","volume":"118","author":"A Regueira","year":"2021","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref107","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0378-4754(95)00127-1","article-title":"Mechanistic mathematical models of microbial growth in bioreactors and in natural soils: Explanation of complex phenomena.","volume":"42","author":"NS Panikov","year":"1996","journal-title":"Math Comput Simul"},{"key":"pcbi.1011391.ref108","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1046\/j.1365-2672.2001.01450.x","article-title":"Heterofermentative pattern and exopolysaccharide production by Lactobacillus helveticus ATCC 15807 in response to environmental pH","volume":"91","author":"MI Torino","year":"2001","journal-title":"J Appl Microbiol"},{"key":"pcbi.1011391.ref109","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3934\/microbiol.2020027","article-title":"Exopolysaccharide production by lactic acid bacteria: the manipulation of environmental stresses for industrial applications.","volume":"6","author":"P-T Nguyen","year":"2020","journal-title":"AIMS Microbiol"},{"key":"pcbi.1011391.ref110","doi-asserted-by":"crossref","first-page":"119365","DOI":"10.1016\/j.watres.2022.119365","article-title":"Predicting the impact of temperature on metabolic fluxes using resource allocation modelling: Application to polyphosphate accumulating organisms","volume":"228","author":"T P\u00e1ez-Watson","year":"2023","journal-title":"Water Res"},{"key":"pcbi.1011391.ref111","article-title":"Dynamic metagenome-scale metabolic modeling of a yogurt bacterial community","author":"S Qiu","year":"2023","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1011391.ref112","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature02456","article-title":"Integrating high-throughput and computational data elucidates bacterial networks","volume":"429","author":"MW Covert","year":"2004","journal-title":"Nature"},{"key":"pcbi.1011391.ref113","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1101\/gr.4083206","article-title":"Integrated analysis of regulatory and metabolic networks reveals novel regulatory mechanisms in Saccharomyces cerevisiae","volume":"16","author":"MJ Herrg\u00e5rd","year":"2006","journal-title":"Genome Res"},{"key":"pcbi.1011391.ref114","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1752-0509-2-20","article-title":"Reconstruction and analysis of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis","volume":"2","author":"A Goelzer","year":"2008","journal-title":"BMC Syst Biol"},{"key":"pcbi.1011391.ref115","doi-asserted-by":"crossref","first-page":"17845","DOI":"10.1073\/pnas.1005139107","article-title":"Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis","volume":"107","author":"S Chandrasekaran","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011391.ref116","doi-asserted-by":"crossref","first-page":"110317","DOI":"10.1016\/j.jtbi.2020.110317","article-title":"Regulatory dynamic enzyme-cost flux balance analysis: A unifying framework for constraint-based modeling","volume":"501","author":"L Liu","year":"2020","journal-title":"J Theor Biol"},{"key":"pcbi.1011391.ref117","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1039\/c3mb25489e","article-title":"Bridging the layers: towards integration of signal transduction, regulation and metabolism into mathematical models","volume":"9","author":"E Gon\u00e7alves","year":"2013","journal-title":"Mol Biosyst"},{"key":"pcbi.1011391.ref118","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.carbpol.2018.10.063","article-title":"The exopolysaccharide properties and structures database: EPS-DB. Application to bacterial exopolysaccharides","volume":"205","author":"J Birch","year":"2019","journal-title":"Carbohydr Polym"},{"key":"pcbi.1011391.ref119","doi-asserted-by":"crossref","first-page":"D233","DOI":"10.1093\/nar\/gkn663","article-title":"The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics.","volume":"37","author":"BL Cantarel","year":"2009","journal-title":"Nucleic Acids Res"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011391","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T17:23:49Z","timestamp":1692897829000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011391"}},"subtitle":[],"editor":[{"given":"Christos A.","family":"Ouzounis","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2023,8,24]]},"references-count":119,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011391","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,24]]}}}