{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:19:26Z","timestamp":1767179966405,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009234","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000}}],"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003030","name":"ag\u00e8ncia de gesti\u00f3 d\u2019ajuts universitaris i de recerca","doi-asserted-by":"publisher","award":["2017SGR1033"],"award-info":[{"award-number":["2017SGR1033"]}],"id":[{"id":"10.13039\/501100003030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CIBEREHD-CB17\/04\/00023"],"award-info":[{"award-number":["CIBEREHD-CB17\/04\/00023"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PT17\/0009\/0018"],"award-info":[{"award-number":["PT17\/0009\/0018"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["SAF2017-89673-R"],"award-info":[{"award-number":["SAF2017-89673-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004837","name":"ministerio de ciencia e innovaci\u00f3n","doi-asserted-by":"crossref","award":["PID2020-115051RB-I00"],"award-info":[{"award-number":["PID2020-115051RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020636","name":"Ministerio de Educaci\u00f3n y Formaci\u00f3n Profesional","doi-asserted-by":"crossref","award":["FPU14-05992"],"award-info":[{"award-number":["FPU14-05992"]}],"id":[{"id":"10.13039\/501100020636","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003741","name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats","doi-asserted-by":"publisher","award":["ICREA Academia 2015"],"award-info":[{"award-number":["ICREA Academia 2015"]}],"id":[{"id":"10.13039\/501100003741","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009234","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T13:37:02Z","timestamp":1627047422000},"page":"e1009234","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrating systemic and molecular levels to infer\u00a0key drivers sustaining metabolic adaptations"],"prefix":"10.1371","volume":"17","author":[{"given":"Pedro","family":"de Atauri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-2686","authenticated-orcid":true,"given":"M\u00edriam","family":"Tarrado-Castellarnau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7322-9736","authenticated-orcid":true,"given":"Josep","family":"Tarrag\u00f3-Celada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-9595","authenticated-orcid":true,"given":"Carles","family":"Foguet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3206-7010","authenticated-orcid":true,"given":"Effrosyni","family":"Karakitsou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6289-9678","authenticated-orcid":true,"given":"Josep Joan","family":"Centelles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-4633","authenticated-orcid":true,"given":"Marta","family":"Cascante","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"issue":"2","key":"pcbi.1009234.ref001","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/s42255-019-0032-0","article-title":"Metabolic signatures of cancer cells and stem cells","volume":"1","author":"AM Intlekofer","year":"2019","journal-title":"Nat Metab"},{"issue":"38","key":"pcbi.1009234.ref002","doi-asserted-by":"crossref","first-page":"62726","DOI":"10.18632\/oncotarget.10911","article-title":"Oncogenic regulation of tumor metabolic reprogramming","volume":"7","author":"M Tarrado-Castellarnau","year":"2016","journal-title":"Oncotarget"},{"issue":"4","key":"pcbi.1009234.ref003","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11306-018-1335-y","article-title":"From correlation to causation: analysis of metabolomics data using systems biology approaches","volume":"14","author":"A Rosato","year":"2018","journal-title":"Metabolomics"},{"key":"pcbi.1009234.ref004","doi-asserted-by":"crossref","first-page":"115371","DOI":"10.1016\/j.trac.2018.12.025","article-title":"Tracing metabolic fluxes using mass spectrometry: Stable isotope-resolved metabolomics in health and disease","volume":"120","author":"C Balcells","year":"2019","journal-title":"Trends in Analytical Chemistry"},{"key":"pcbi.1009234.ref005","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.copbio.2014.12.003","article-title":"How to measure metabolic fluxes: a taxonomic guide for (13)C fluxomics","volume":"34","author":"S Niedenfuhr","year":"2015","journal-title":"Curr Opin Biotechnol"},{"issue":"3","key":"pcbi.1009234.ref006","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.1009234.ref007","doi-asserted-by":"crossref","DOI":"10.1002\/9781119188902","volume-title":"Optimization methods in metabolic networks","author":"CD Maranas","year":"2016"},{"issue":"6","key":"pcbi.1009234.ref008","first-page":"1218","article-title":"Seeing the wood for the trees: a forest of methods for optimization and omic-network integration in metabolic modelling","volume":"19","author":"S Vijayakumar","year":"2018","journal-title":"Brief Bioinform"},{"key":"pcbi.1009234.ref009","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.coisb.2019.03.009","article-title":"Metabolomics in systems medicine: an overview of methods and applications","volume":"15","author":"E Karakitsou","year":"2019","journal-title":"Curr Opin Syst Biol"},{"key":"pcbi.1009234.ref010","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"},{"issue":"8","key":"pcbi.1009234.ref011","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.biotechadv.2017.09.005","article-title":"Formulation, construction and analysis of kinetic models of metabolism: A review of modelling frameworks","volume":"35","author":"PA Saa","year":"2017","journal-title":"Biotechnol Adv"},{"key":"pcbi.1009234.ref012","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.copbio.2019.02.005","article-title":"Metabolic kinetic modeling provides insight into complex biological questions, but hurdles remain","volume":"59","author":"J Strutz","year":"2019","journal-title":"Curr Opin Biotechnol"},{"key":"pcbi.1009234.ref013","first-page":"45","volume-title":"Fundamentals of Medical Cell Biology","author":"MA Savageau","year":"1992"},{"issue":"17","key":"pcbi.1009234.ref014","doi-asserted-by":"crossref","first-page":"5313","DOI":"10.1046\/j.1432-1327.2000.01527.x","article-title":"Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enzymes? Testing biochemistry","volume":"267","author":"B Teusink","year":"2000","journal-title":"Eur J Biochem"},{"key":"pcbi.1009234.ref015","volume-title":"Fundamentals of enzyme kinetics","author":"A. Cornish-Bowden","year":"2012","edition":"4"},{"key":"pcbi.1009234.ref016","volume-title":"Understanding the Control of Metabolism","author":"DA Fell","year":"1996"},{"issue":"30","key":"pcbi.1009234.ref017","doi-asserted-by":"crossref","first-page":"13544","DOI":"10.1021\/acs.iecr.9b00818","article-title":"Control Theory Concepts for Modeling Uncertainty in Enzyme Kinetics of Biochemical Networks","volume":"58","author":"L Miskovic","year":"2019","journal-title":"Ind Eng Chem Res"},{"key":"pcbi.1009234.ref018","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4613-1161-4","volume-title":"The regulation of cellular systems","author":"R Heinrich","year":"1996"},{"key":"pcbi.1009234.ref019","volume-title":"Systems Biology: An Introduction to Metabolic Control Analysis.","author":"H. Sauro","year":"2019"},{"key":"pcbi.1009234.ref020","volume-title":"Computational analysis of biochemical systems: a practical guide for biochemists and molecular biologists","author":"EO Voit","year":"2000"},{"issue":"2","key":"pcbi.1009234.ref021","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0025-5564(87)90008-3","article-title":"Biochemical systems theory and metabolic control theory: 2. the role of summation and connectivity relationships","volume":"86","author":"MA Savageau","year":"1987","journal-title":"Mathematical Biosciences"},{"issue":"3","key":"pcbi.1009234.ref022","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.jbiotec.2010.01.026","article-title":"Optimization and evolution in metabolic pathways: global optimization techniques in Generalized Mass Action models","volume":"149","author":"A Sorribas","year":"2010","journal-title":"J Biotechnol"},{"issue":"8","key":"pcbi.1009234.ref023","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.cor.2009.02.021","article-title":"Optimization of biochemical systems through mathematical programming: Methods and applications","volume":"37","author":"J Vera","year":"2010","journal-title":"Computers & Operations Research"},{"issue":"1","key":"pcbi.1009234.ref024","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejor.2012.07.026","article-title":"Steady-state optimization of biochemical systems through geometric programming","volume":"225","author":"G. Xu","year":"2013","journal-title":"Eur J Oper Res"},{"key":"pcbi.1009234.ref025","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.compchemeng.2017.06.019","article-title":"Steady-state optimization of biochemical systems by bi-level programming","volume":"106","author":"G Xu","year":"2017","journal-title":"Comput Chem Eng"},{"issue":"12","key":"pcbi.1009234.ref026","doi-asserted-by":"crossref","first-page":"i214","DOI":"10.1093\/bioinformatics\/btv243","article-title":"Refined elasticity sampling for Monte Carlo-based identification of stabilizing network patterns","volume":"31","author":"D Childs","year":"2015","journal-title":"Bioinformatics"},{"key":"pcbi.1009234.ref027","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/msb4100186","article-title":"The stability and robustness of metabolic states: identifying stabilizing sites in metabolic networks","volume":"3","author":"S Grimbs","year":"2007","journal-title":"Mol Syst Biol"},{"issue":"8","key":"pcbi.1009234.ref028","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.tibtech.2010.05.003","article-title":"Production of biofuels and biochemicals: in need of an ORACLE","volume":"28","author":"L Miskovic","year":"2010","journal-title":"Trends Biotechnol"},{"issue":"1","key":"pcbi.1009234.ref029","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0025-5564(94)00092-E","article-title":"Comparative characterization of the fermentation pathway of Saccharomyces cerevisiae using biochemical systems theory and metabolic control analysis: model definition and nomenclature","volume":"130","author":"R Curto","year":"1995","journal-title":"Math Biosci"},{"issue":"2","key":"pcbi.1009234.ref030","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/0014-5793(88)80775-0","article-title":"How do external parameters control fluxes and concentrations of metabolites? An additional relationship in the theory of metabolic control","volume":"232","author":"BN Kholodenko","year":"1988","journal-title":"FEBS Lett"},{"issue":"2","key":"pcbi.1009234.ref031","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0025-5564(89)90067-9","article-title":"Use of implicit methods from general sensitivity theory to develop a systematic approach to metabolic control. I. Unbranched pathways","volume":"94","author":"M Cascante","year":"1989","journal-title":"Math Biosci"},{"issue":"2","key":"pcbi.1009234.ref032","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/0025-5564(89)90068-0","article-title":"Use of implicit methods from general sensitivity theory to develop a systematic approach to metabolic control. II. Complex systems","volume":"94","author":"M Cascante","year":"1989","journal-title":"Math Biosci"},{"issue":"1","key":"pcbi.1009234.ref033","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1432-1033.1991.tb21071.x","article-title":"Quantitative assessment of regulation in metabolic systems","volume":"200","author":"JH Hofmeyr","year":"1991","journal-title":"Eur J Biochem"},{"issue":"2\u20133","key":"pcbi.1009234.ref034","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/(SICI)1097-0290(19980420)58:2\/3<154::AID-BIT7>3.0.CO;2-K","article-title":"Application of mathematical tools for metabolic design of microbial ethanol production","volume":"58","author":"V Hatzimanikatis","year":"1998","journal-title":"Biotechnol Bioeng"},{"issue":"5","key":"pcbi.1009234.ref035","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1002\/aic.690420509","article-title":"Analysis and design of metabolic reaction networks via mixed-integer linear optimization","volume":"42","author":"V Hatzimanikatis","year":"1996","journal-title":"AIChE J"},{"issue":"2","key":"pcbi.1009234.ref036","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/(SICI)1097-0290(19970420)54:2<91::AID-BIT1>3.0.CO;2-Q","article-title":"Effects of spatiotemporal variations on metabolic control: approximate analysis using (log)linear kinetic models","volume":"54","author":"V Hatzimanikatis","year":"1997","journal-title":"Biotechnol Bioeng"},{"issue":"5","key":"pcbi.1009234.ref037","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/bit.260400504","article-title":"Optimization in integrated biochemical systems","volume":"40","author":"EO Voit","year":"1992","journal-title":"Biotechnol Bioeng"},{"issue":"3","key":"pcbi.1009234.ref038","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1006\/jtbi.1996.0160","article-title":"MCA has more to say","volume":"182","author":"V Hatzimanikatis","year":"1996","journal-title":"J Theor Biol"},{"issue":"4","key":"pcbi.1009234.ref039","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/(SICI)1097-0290(19961120)52:4<485::AID-BIT4>3.0.CO;2-L","article-title":"Optimization of regulatory architectures in metabolic reaction networks","volume":"52","author":"V Hatzimanikatis","year":"1996","journal-title":"Biotechnol Bioeng"},{"issue":"5","key":"pcbi.1009234.ref040","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/(SICI)1097-0290(19970905)55:5<758::AID-BIT6>3.0.CO;2-A","article-title":"An indirect optimization method for biochemical systems: Description of method and application to the maximization of the rate of ethanol, glycerol, and carbohydrate production in Saccharomyces cerevisiae","volume":"55","author":"NV Torres","year":"1997","journal-title":"Biotechnol Bioeng"},{"issue":"3","key":"pcbi.1009234.ref041","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/bit.10676","article-title":"Multicriteria optimization of biochemical systems by linear programming: application to production of ethanol by Saccharomyces cerevisiae","volume":"83","author":"J Vera","year":"2003","journal-title":"Biotechnol Bioeng"},{"issue":"14","key":"pcbi.1009234.ref042","doi-asserted-by":"crossref","first-page":"7562","DOI":"10.1016\/j.amc.2012.01.023","article-title":"Bi-objective optimization of biochemical systems by linear programming","volume":"218","author":"G. Xu","year":"2012","journal-title":"Appl Math Comput"},{"issue":"7","key":"pcbi.1009234.ref043","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1002\/bit.10436","article-title":"Modeling, optimization and experimental assessment of continuous L-(-)-carnitine production by Escherichia coli cultures","volume":"80","author":"F Alvarez-Vasquez","year":"2002","journal-title":"Biotechnol Bioeng"},{"key":"pcbi.1009234.ref044","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1742-4682-4-38","article-title":"Optimization of biotechnological systems through geometric programming","volume":"4","author":"A Marin-Sanguino","year":"2007","journal-title":"Theor Biol Med Model"},{"key":"pcbi.1009234.ref045","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/719496","article-title":"An Improved Geometric Programming Approach for Optimization of Biochemical Systems","volume":"2014","author":"G Xu","year":"2014","journal-title":"J Appl Math"},{"key":"pcbi.1009234.ref046","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1186\/1471-2105-10-386","article-title":"Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses","volume":"10","author":"G Guillen-Gosalbez","year":"2009","journal-title":"BMC Bioinf"},{"issue":"9","key":"pcbi.1009234.ref047","doi-asserted-by":"crossref","first-page":"e43487","DOI":"10.1371\/journal.pone.0043487","article-title":"Identifying the preferred subset of enzymatic profiles in nonlinear kinetic metabolic models via multiobjective global optimization and Pareto filters","volume":"7","author":"C Pozo","year":"2012","journal-title":"PLoS One"},{"issue":"1\u20132","key":"pcbi.1009234.ref048","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0014-5793(97)01347-1","article-title":"Comparison of control analysis data using different approaches: modelling and experiments with muscle extract","volume":"418","author":"J Puigjaner","year":"1997","journal-title":"FEBS Lett"},{"issue":"1","key":"pcbi.1009234.ref049","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/BF00928908","article-title":"A model of the pentose phosphate pathway in rat liver cells","volume":"142","author":"L Sabate","year":"1995","journal-title":"Mol Cell Biochem"},{"issue":"10","key":"pcbi.1009234.ref050","doi-asserted-by":"crossref","first-page":"940","DOI":"10.15252\/msb.20167321","article-title":"De novo MYC addiction as an adaptive response of cancer cells to CDK4\/6 inhibition","volume":"13","author":"M Tarrado-Castellarnau","year":"2017","journal-title":"Mol Syst Biol"},{"issue":"6","key":"pcbi.1009234.ref051","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1086\/430799","article-title":"Single-gene disorders: what role could moonlighting enzymes play?","volume":"76","author":"G Sriram","year":"2005","journal-title":"Am J Hum Genet"},{"issue":"3","key":"pcbi.1009234.ref052","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jtbi.2007.10.018","article-title":"Kinetic properties required for sustained or paradoxical control of metabolic fluxes under large changes in enzyme activities","volume":"252","author":"F Ortega","year":"2008","journal-title":"J Theor Biol"},{"issue":"4","key":"pcbi.1009234.ref053","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ymben.2003.09.002","article-title":"The effects of alternate optimal solutions in constraint-based genome-scale metabolic models","volume":"5","author":"R Mahadevan","year":"2003","journal-title":"Metab Eng"},{"issue":"5","key":"pcbi.1009234.ref054","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1021\/bp0100880","article-title":"Minimal reaction sets for Escherichia coli metabolism under different growth requirements and uptake environments","volume":"17","author":"AP Burgard","year":"2001","journal-title":"Biotechnol Prog"},{"issue":"2","key":"pcbi.1009234.ref055","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jtbi.2006.12.029","article-title":"An interval approach for dealing with flux distributions and elementary modes activity patterns","volume":"246","author":"F Llaneras","year":"2007","journal-title":"J Theor Biol"},{"key":"pcbi.1009234.ref056","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1186\/1471-2105-11-489","article-title":"Computationally efficient flux variability analysis","volume":"11","author":"S Gudmundsson","year":"2010","journal-title":"BMC Bioinf"},{"issue":"2","key":"pcbi.1009234.ref057","doi-asserted-by":"crossref","first-page":"e1003487","DOI":"10.1371\/journal.pcbi.1003487","article-title":"k-OptForce: integrating kinetics with flux balance analysis for strain design","volume":"10","author":"A Chowdhury","year":"2014","journal-title":"PLoS Comput Biol"},{"issue":"24","key":"pcbi.1009234.ref058","doi-asserted-by":"crossref","first-page":"4248","DOI":"10.1093\/bioinformatics\/bty446","article-title":"Accelerating flux balance calculations in genome-scale metabolic models by localizing the application of loopless constraints","volume":"34","author":"SHJ Chan","year":"2018","journal-title":"Bioinformatics"},{"issue":"3","key":"pcbi.1009234.ref059","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1432-1033.1985.tb08876.x","article-title":"Metabolic control and its analysis. Additional relationships between elasticities and control coefficients","volume":"148","author":"DA Fell","year":"1985","journal-title":"Eur J Biochem"},{"issue":"1","key":"pcbi.1009234.ref060","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/bit.260300115","article-title":"Matrix method for determining steps most rate-limiting to metabolic fluxes in biotechnological processes","volume":"30","author":"HV Westerhoff","year":"1987","journal-title":"Biotechnol Bioeng"},{"issue":"2","key":"pcbi.1009234.ref061","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0022-5193(88)80073-0","article-title":"Metabolic control theory: a structural approach","volume":"135","author":"C. Reder","year":"1988","journal-title":"J Theor Biol"},{"issue":"2","key":"pcbi.1009234.ref062","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0022-5193(89)80225-5","article-title":"The matrix method of metabolic control analysis: its validity for complex pathway structures","volume":"136","author":"JR Small","year":"1989","journal-title":"J Theor Biol"},{"issue":"1","key":"pcbi.1009234.ref063","first-page":"125","article-title":"Inferring dynamic properties of biochemical reaction networks from structural knowledge","volume":"15","author":"E Klipp","year":"2004","journal-title":"Genome Inform"},{"issue":"9","key":"pcbi.1009234.ref064","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1093\/bioinformatics\/16.9.786","article-title":"Extending the method of mathematically controlled comparison to include numerical comparisons","volume":"16","author":"R Alves","year":"2000","journal-title":"Bioinformatics"},{"issue":"11","key":"pcbi.1009234.ref065","doi-asserted-by":"crossref","first-page":"e79244","DOI":"10.1371\/journal.pone.0079244","article-title":"What can we learn from global sensitivity analysis of biochemical systems?","volume":"8","author":"E Kent","year":"2013","journal-title":"PLoS One."},{"issue":"6","key":"pcbi.1009234.ref066","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1529\/biophysj.104.048090","article-title":"Metabolic control analysis under uncertainty: framework development and case studies","volume":"87","author":"L Wang","year":"2004","journal-title":"Biophys J"},{"issue":"9","key":"pcbi.1009234.ref067","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1002\/biot.201300091","article-title":"Towards kinetic modeling of genome-scale metabolic networks without sacrificing stoichiometric, thermodynamic and physiological constraints.","volume":"8","author":"A Chakrabarti","year":"2013","journal-title":"Biotechnol J"},{"issue":"32","key":"pcbi.1009234.ref068","doi-asserted-by":"crossref","first-page":"11868","DOI":"10.1073\/pnas.0600013103","article-title":"Structural kinetic modeling of metabolic networks","volume":"103","author":"R Steuer","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1009234.ref069","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1182\/blood-2004-07-2958","article-title":"Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1","volume":"105","author":"DJ Manalo","year":"2005","journal-title":"Blood"},{"issue":"22","key":"pcbi.1009234.ref070","doi-asserted-by":"crossref","first-page":"15215","DOI":"10.1074\/jbc.M511408200","article-title":"Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways","volume":"281","author":"GP Elvidge","year":"2006","journal-title":"J Biol Chem"},{"issue":"14","key":"pcbi.1009234.ref071","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1093\/nar\/gkp425","article-title":"An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia","volume":"37","author":"Y Benita","year":"2009","journal-title":"Nucleic Acids Res"},{"issue":"16","key":"pcbi.1009234.ref072","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.18632\/oncotarget.2213","article-title":"Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth","volume":"5","author":"J Chesney","year":"2014","journal-title":"Oncotarget"},{"issue":"7239","key":"pcbi.1009234.ref073","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nature07823","article-title":"c-Myc suppression of miR-23a\/b enhances mitochondrial glutaminase expression and glutamine metabolism","volume":"458","author":"P Gao","year":"2009","journal-title":"Nature"},{"key":"pcbi.1009234.ref074","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-79240-8","volume-title":"Principles and Models of Biological Transport","author":"MH Friedman","year":"2008","edition":"2"},{"key":"pcbi.1009234.ref075","author":"WD Stein","year":"2015","edition":"2"},{"issue":"1","key":"pcbi.1009234.ref076","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1006\/jtbi.1993.1177","article-title":"Metabolic Control Design","volume":"165","author":"L. Acerenza","year":"1993","journal-title":"J theor Biol"},{"issue":"12","key":"pcbi.1009234.ref077","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1093\/bioinformatics\/btq141","article-title":"Modular rate laws for enzymatic reactions: thermodynamics, elasticities and implementation","volume":"26","author":"W Liebermeister","year":"2010","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1009234.ref078","doi-asserted-by":"crossref","first-page":"e1004195","DOI":"10.1371\/journal.pcbi.1004195","article-title":"A general framework for thermodynamically consistent parameterization and efficient sampling of enzymatic reactions","volume":"11","author":"P Saa","year":"2015","journal-title":"PLoS Comput Biol"},{"issue":"49","key":"pcbi.1009234.ref079","doi-asserted-by":"crossref","first-page":"16280","DOI":"10.1021\/jp108412s","article-title":"Kinetic and thermodynamic aspects of enzyme control and regulation","volume":"114","author":"JM Rohwer","year":"2010","journal-title":"J Phys Chem B"},{"issue":"5","key":"pcbi.1009234.ref080","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/BF02110188","article-title":"Metabolic regulation: a control analytic perspective","volume":"27","author":"JH Hofmeyr","year":"1995","journal-title":"J Bioenerg Biomembr"},{"issue":"4","key":"pcbi.1009234.ref081","first-page":"377","article-title":"The reversible Hill equation: how to incorporate cooperative enzymes into metabolic models","volume":"13","author":"JH Hofmeyr","year":"1997","journal-title":"CABIOS"},{"key":"pcbi.1009234.ref082","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-86602-9","volume-title":"Enzyme handbook.","author":"TE Barman","year":"1969"},{"key":"pcbi.1009234.ref083","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-662-11691-3","volume-title":"Enzyme handbook: supplement.","author":"TE Barman","year":"1974"},{"key":"pcbi.1009234.ref084","doi-asserted-by":"crossref","DOI":"10.1002\/9783527618330","volume-title":"Handbook of enzyme inhibitors","author":"H. Zollner","year":"1999","edition":"3"},{"key":"pcbi.1009234.ref085","doi-asserted-by":"crossref","first-page":"D764","DOI":"10.1093\/nar\/gks1049","article-title":"BRENDA in 2013: integrated reactions, kinetic data, enzyme function data, improved disease classification: new options and contents in BRENDA","volume":"41","author":"I Schomburg","year":"2013","journal-title":"Nucleic Acids Res"},{"issue":"30","key":"pcbi.1009234.ref086","doi-asserted-by":"crossref","first-page":"9426","DOI":"10.1021\/bi020110d","article-title":"Evolution of the allosteric ligand sites of mammalian phosphofructo-1-kinase","volume":"41","author":"RG Kemp","year":"2002","journal-title":"Biochemistry"},{"issue":"7","key":"pcbi.1009234.ref087","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.biocel.2010.02.005","article-title":"Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells","volume":"43","author":"S. Mazurek","year":"2011","journal-title":"Int J Biochem Cell Biol"},{"key":"pcbi.1009234.ref088","doi-asserted-by":"crossref","first-page":"8","DOI":"10.2174\/1874940201003010008","article-title":"Inhibitors of Pyruvate Carboxylase","volume":"3","author":"TN Zeczycki","year":"2010","journal-title":"Open Enzym Inhib J"},{"issue":"2","key":"pcbi.1009234.ref089","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.abb.2011.11.015","article-title":"Regulation of the structure and activity of pyruvate carboxylase by acetyl CoA","volume":"519","author":"A Adina-Zada","year":"2012","journal-title":"Arch Biochem Biophys"},{"issue":"1","key":"pcbi.1009234.ref090","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/BF01732163","article-title":"The steady state activity of succinate dehydrogenase in the presence of opposing effectors. I. The effect of L malate and CoQH2 on the enzymic activity","volume":"7","author":"M Gutman","year":"1975","journal-title":"Mol Cell Biochem"},{"issue":"3","key":"pcbi.1009234.ref091","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF01731407","article-title":"The steady state activity of succinate dehydrogenase in the presence of opposing effectors. II. Reductive activation of succinate dehydrogenase in presence of oxaloacetate","volume":"7","author":"M Gutman","year":"1975","journal-title":"Mol Cell Biochem"},{"issue":"2","key":"pcbi.1009234.ref092","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.abb.2010.09.002","article-title":"The activity of phosphate-dependent glutaminase from the rat small intestine is modulated by ADP and is dependent on integrity of mitochondria","volume":"504","author":"B Masola","year":"2010","journal-title":"Arch Biochem Biophys"},{"issue":"4","key":"pcbi.1009234.ref093","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.neuint.2010.10.017","article-title":"The structure and allosteric regulation of glutamate dehydrogenase","volume":"59","author":"M Li","year":"2011","journal-title":"Neurochem Int"},{"issue":"2","key":"pcbi.1009234.ref094","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0014-5793(73)80559-9","article-title":"Calculation of the intracellular distribution of Acetyl CoA and CoA, based on the use of citrate synthase as an equilibrium enzyme","volume":"29","author":"KA Gumaa","year":"1973","journal-title":"FEBS Letters"},{"key":"pcbi.1009234.ref095","doi-asserted-by":"crossref","first-page":"D750","DOI":"10.1093\/nar\/gkp889","article-title":"BioNumbers\u2014the database of key numbers in molecular and cell biology","volume":"38","author":"R Milo","year":"2010","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009234","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T06:44:44Z","timestamp":1699253084000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009234"}},"subtitle":[],"editor":[{"given":"Kiran Raosaheb","family":"Patil","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":95,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009234","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]}}}