{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T16:14:14Z","timestamp":1777047254976,"version":"3.51.4"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","funder":[{"DOI":"10.13039\/100009465","name":"Corporaci\u00f3n de Fomento de la Producci\u00f3n","doi-asserted-by":"publisher","award":["Project 11CEII-9568"],"award-info":[{"award-number":["Project 11CEII-9568"]}],"id":[{"id":"10.13039\/100009465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["22140230"],"award-info":[{"award-number":["22140230"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["21140759"],"award-info":[{"award-number":["21140759"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2017,12]]},"DOI":"10.1186\/s12918-017-0408-2","type":"journal-article","created":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T13:09:11Z","timestamp":1487682551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Dynamic genome-scale metabolic modeling of the yeast Pichia pastoris"],"prefix":"10.1186","volume":"11","author":[{"given":"Francisco","family":"Saitua","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Ricardo","family":"P\u00e9rez-Correa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Agosin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,2,21]]},"reference":[{"issue":"7","key":"408_CR1","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/nbt.3040","volume":"32","author":"G Walsh","year":"2014","unstructured":"Walsh G. Biopharmaceutical benchmarks 2014. Nat Biotechnol. 2014;32(7):992\u20131000.","journal-title":"Nat Biotechnol"},{"key":"408_CR2","volume-title":"Global markets for enzymes in industrial applications - report overview","author":"BCC Research","year":"2014","unstructured":"BCC Research. Global markets for enzymes in industrial applications - report overview. 2014 [Online]. Available: http:\/\/www.bccresearch.com\/market-research\/biotechnology\/enzymes-industrial-applications-bio030h.html . [Accessed: 07 Dec 2015]."},{"key":"408_CR3","volume-title":"Industrial Enzymes Market by Type (Carbohydrases, Proteases, Non-starch Polysaccharides & Others), Application (Food & Beverage, Cleaning Agents, Animal Feed & Others), Brands & by Region - Globlar Trends and Forecasts to 2020","author":"Markets and Markets","year":"2015","unstructured":"Markets and Markets. Industrial Enzymes Market by Type (Carbohydrases, Proteases, Non-starch Polysaccharides & Others), Application (Food & Beverage, Cleaning Agents, Animal Feed & Others), Brands & by Region - Globlar Trends and Forecasts to 2020. 2015 [Online]. Available: http:\/\/www.marketsandmarkets.com\/Market-Reports\/industrial-enzymes-market-237327836.html . [Accessed: 07 Dec 2015]."},{"issue":"5","key":"408_CR4","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.drudis.2013.11.008","volume":"19","author":"TW Overton","year":"2014","unstructured":"Overton TW. Recombinant protein production in bacterial hosts. Drug Discov Today. 2014;19(5):590\u2013601.","journal-title":"Drug Discov Today"},{"issue":"4","key":"408_CR5","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/biot.201300305","volume":"9","author":"A Maccani","year":"2014","unstructured":"Maccani A, Landes N, Stadlmayr G, Maresch D, Leitner C, Maurer M, Gasser B, Ernst W, Kunert R, Mattanovich D. Pichia pastoris secretes recombinant proteins less efficiently than Chinese hamster ovary cells but allows higher space-time yields for less complex proteins. Biotechnol J. 2014;9(4):526\u201337.","journal-title":"Biotechnol J"},{"key":"408_CR6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1475-2859-8-17","volume":"8","author":"N Ferrer-Miralles","year":"2009","unstructured":"Ferrer-Miralles N, Domingo-Esp\u00edn J, Corchero JL, V\u00e1zquez E, Villaverde A. Microbial factories for recombinant pharmaceuticals. Microb Cell Fact. 2009;8:17.","journal-title":"Microb Cell Fact"},{"issue":"2","key":"408_CR7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.biotechadv.2012.09.001","volume":"31","author":"JL Corchero","year":"2013","unstructured":"Corchero JL, Gasser B, Resina D, Smith W, Parrilli E, V\u00e1zquez F, Abasolo I, Giuliani M, J\u00e4ntti J, Ferrer P, Saloheimo M, Mattanovich D, Schwartz S, Tutino ML, Villaverde A. Unconventional microbial systems for the cost-efficient production of high-quality protein therapeutics. Biotechnol Adv. 2013;31(2):140\u201353.","journal-title":"Biotechnol Adv"},{"issue":"2","key":"408_CR8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/jmr.687","volume":"18","author":"R Daly","year":"2005","unstructured":"Daly R, Hearn MTW. Expression of heterologous proteins in Pichia pastoris: a useful experimental tool in protein engineering and production. J Mol Recognit. 2005;18(2):119\u201338.","journal-title":"J Mol Recognit"},{"issue":"1","key":"408_CR9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1574-6976.2000.tb00532.x","volume":"24","author":"JL Cereghino","year":"2000","unstructured":"Cereghino JL, Cregg JM. Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol Rev. 2000;24(1):45\u201366.","journal-title":"FEMS Microbiol Rev"},{"issue":"1","key":"408_CR10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yrtph.2006.02.001","volume":"45","author":"V Ciofalo","year":"2006","unstructured":"Ciofalo V, Barton N, Kreps J, Coats I, Shanahan D. Safety evaluation of a lipase enzyme preparation, expressed in Pichia pastoris, intended for use in the degumming of edible vegetable oil. Regul Toxicol Pharmacol. 2006;45(1):1\u20138.","journal-title":"Regul Toxicol Pharmacol"},{"issue":"6","key":"408_CR11","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3136\/fstr.16.585","volume":"16","author":"T Masuda","year":"2010","unstructured":"Masuda T, Ide N, Ohta K, Kitabatake N. High-yield secretion of the recombinant sweet-tasting protein Thaumatin I. Food Sci Technol Res. 2010;16(6):585\u201392.","journal-title":"Food Sci Technol Res"},{"key":"408_CR12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bej.2014.12.003","volume":"95","author":"P \u00c7al\u0131k","year":"2015","unstructured":"\u00c7al\u0131k P, Ata \u00d6, G\u00fcne\u015f H, Massahi A, Boy E, Keskin A, \u00d6zt\u00fcrk S, Zerze GH, \u00d6zdamar TH. Recombinant protein production in Pichia pastoris under glyceraldehyde-3-phosphate dehydrogenase promoter: from carbon source metabolism to bioreactor operation parameters. Biochem Eng J. 2015;95:20\u201336.","journal-title":"Biochem Eng J"},{"key":"408_CR13","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1475-2859-8-29","volume":"8","author":"D Mattanovich","year":"2009","unstructured":"Mattanovich D, Graf A, Stadlmann J, Dragosits M, Redl A, Maurer M, Kleinheinz M, Sauer M, Altmann F, Gasser B. Genome, secretome and glucose transport highlight unique features of the protein production host Pichia pastoris. Microb Cell Fact. 2009;8:29.","journal-title":"Microb Cell Fact"},{"issue":"6","key":"408_CR14","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/1574-6976.12020","volume":"37","author":"M Delic","year":"2013","unstructured":"Delic M, Valli M, Graf AB, Pfeffer M, Mattanovich D, Gasser B. The secretory pathway: exploring yeast diversity. FEMS Microbiol Rev. 2013;37(6):872\u2013914.","journal-title":"FEMS Microbiol Rev"},{"issue":"1","key":"408_CR15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1006\/prep.1997.0765","volume":"11","author":"M Hasslacher","year":"1997","unstructured":"Hasslacher M, Schall M, Hayn M, Bona R, Rumbold K, L\u00fcckl J, Griengl H, Kohlwein SD, Schwab H. High-level intracellular expression of hydroxynitrile lyase from the tropical rubber TreeHevea brasiliensisin microbial hosts. Protein Expr Purif. 1997;11(1):61\u201371.","journal-title":"Protein Expr Purif"},{"issue":"2","key":"408_CR16","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/bit.22836","volume":"107","author":"J Heyland","year":"2010","unstructured":"Heyland J, Fu J, Blank LM, Schmid A. Quantitative physiology of Pichia pastoris during glucose-limited high-cell density fed-batch cultivation for recombinant protein production. Biotechnol Bioeng. 2010;107(2):357\u201368.","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"408_CR17","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12934-015-0356-8","volume":"14","author":"E \u010ciplys","year":"2015","unstructured":"\u010ciplys E, \u017ditkus E, Gold LI, Daubriac J, Pavlides SC, H\u00f8jrup P, Houen G, Wang W-A, Michalak M, Slibinskas R. High-level secretion of native recombinant human calreticulin in yeast. Microb Cell Fact. 2015;14(1):165.","journal-title":"Microb Cell Fact"},{"key":"408_CR18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/1097-0290(20010405)73:1<74::AID-BIT1038>3.0.CO;2-V","volume":"73","author":"Y Wang","year":"2001","unstructured":"Wang Y, Liang ZH, Zhang YS, Yao SY, Xu YG, Tang YH, Zhu SQ, Cui DF, Feng YM. Human insulin from a precursor overexpressed in the methylotrophic yeast Pichia pastoris and a simple procedure for purifying the expression product. Biotechnol Bioeng. 2001;73:74\u20139.","journal-title":"Biotechnol Bioeng"},{"key":"408_CR19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2146\/news100005","volume":"67","author":"CA Thompson","year":"2010","unstructured":"Thompson CA. FDA approves kallikrein inhibitor to treat hereditary angioedema. Am J Health Pharm. 2010;67:93.","journal-title":"Am J Health Pharm"},{"issue":"3","key":"408_CR20","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1089\/ars.2014.5844","volume":"21","author":"M Delic","year":"2014","unstructured":"Delic M, G\u00f6ngrich R, Mattanovich D, Gasser B. Engineering of protein folding and secretion-strategies to overcome bottlenecks for efficient production of recombinant proteins. Antioxid Redox Signal. 2014;21(3):414\u201337.","journal-title":"Antioxid Redox Signal"},{"issue":"2","key":"408_CR21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2217\/fmb.12.133","volume":"8","author":"B Gasser","year":"2013","unstructured":"Gasser B, Prielhofer R, Marx H, Maurer M, Nocon J, Steiger M, Puxbaum V, Sauer M, Mattanovich D. Pichia pastoris : protein production host and model organism for biomedical research. Future Microbiol. 2013;8(2):191\u2013208.","journal-title":"Future Microbiol"},{"key":"408_CR22","first-page":"1","volume":"2015","author":"J-R Wang","year":"2015","unstructured":"Wang J-R, Li Y-Y, Liu D-N, Liu J-S, Li P, Chen L-Z, Xu S-D. Codon optimization significantly improves the expression level of \u03b1 -Amylase gene from Bacillus licheniformis in Pichia pastoris. Biomed Res Int. 2015;2015:1\u20139.","journal-title":"Biomed Res Int"},{"issue":"1","key":"408_CR23","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1475-2859-12-5","volume":"12","author":"R Prielhofer","year":"2013","unstructured":"Prielhofer R, Maurer M, Klein J, Wenger J, Kiziak C, Gasser B, Mattanovich D. Induction without methanol: novel regulated promoters enable high-level expression in Pichia pastoris. Microb Cell Fact. 2013;12(1):5.","journal-title":"Microb Cell Fact"},{"issue":"8","key":"408_CR24","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1002\/bit.23114","volume":"108","author":"J Heyland","year":"2011","unstructured":"Heyland J, Fu J, Blank LM, Schmid A. Carbon metabolism limits recombinant protein production in Pichia pastoris. Biotechnol Bioeng. 2011;108(8):1942\u201353.","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"408_CR25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/bit.21763","volume":"100","author":"K Baumann","year":"2008","unstructured":"Baumann K, Maurer M, Dragosits M, Cos O, Ferrer P, Mattanovich D. Hypoxic fed-batch cultivation ofPichia pastoris increases specific and volumetric productivity of recombinant proteins. Biotechnol Bioeng. 2008;100(1):177\u201383.","journal-title":"Biotechnol Bioeng"},{"key":"408_CR26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1475-2859-5-37","volume":"5","author":"M Maurer","year":"2006","unstructured":"Maurer M, K\u00fchleitner M, Gasser B, Mattanovich D. Versatile modeling and optimization of fed batch processes for the production of secreted heterologous proteins with Pichia pastoris. Microb Cell Fact. 2006;5:37.","journal-title":"Microb Cell Fact"},{"key":"408_CR27","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.biotechadv.2015.05.008","volume":"33","author":"V Looser","year":"2015","unstructured":"Looser V, Bruhlmann B, Bumbak F, Stenger C, Costa M, Camattari A, Fotiadis D, Kovar K. Cultivation strategies to enhance productivity of Pichia pastoris\u202f: a review. Biotechnol Adv. 2015;33:1177\u201393.","journal-title":"Biotechnol Adv"},{"issue":"4","key":"408_CR28","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s002530051412","volume":"51","author":"D Riesenberg","year":"1999","unstructured":"Riesenberg D, Guthke R. High-cell-density cultivation of microorganisms. Appl Microbiol Biotechnol. 1999;51(4):422\u201330.","journal-title":"Appl Microbiol Biotechnol"},{"key":"408_CR29","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4419-9688-6","volume-title":"Bioreaction engineering principles","author":"J Villadsen","year":"2011","unstructured":"Villadsen J, Nielsen J, Lid\u00e9n G. Bioreaction engineering principles. 3rd ed. Nueva York: Springer; 2011.","edition":"3"},{"issue":"1","key":"408_CR30","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1752-0509-5-75","volume":"5","author":"F Vargas","year":"2011","unstructured":"Vargas F, Pizarro F, P\u00e9rez-Correa JR, Agosin E. Expanding a dynamic flux balance model of yeast fermentation to genome-scale. BMC Syst Biol. 2011;5(1):75.","journal-title":"BMC Syst Biol"},{"issue":"2","key":"408_CR31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00449-014-1264-8","volume":"38","author":"C Landi","year":"2015","unstructured":"Landi C, Paciello L, De Alteriis E, Brambilla L, Parascandola P. High cell density culture with S. cerevisiae CEN.PK113-5D for IL-1\u03b2 production: optimization, modeling, and physiological aspects. Bioprocess Biosyst Eng. 2015;38(2):251\u201361.","journal-title":"Bioprocess Biosyst Eng"},{"issue":"3","key":"408_CR32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1567-1364.2009.00507.x","volume":"9","author":"A Graf","year":"2009","unstructured":"Graf A, Dragosits M, Gasser B, Mattanovich D. Yeast systems biotechnology for the production of heterologous proteins. FEMS Yeast Res. 2009;9(3):335\u201348.","journal-title":"FEMS Yeast Res"},{"issue":"5560","key":"408_CR33","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1126\/science.1069492","volume":"295","author":"H Kitano","year":"2002","unstructured":"Kitano H. Systems biology: a brief overview. Science. 2002;295(5560):1662\u20134.","journal-title":"Science"},{"issue":"10","key":"408_CR34","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1128\/AEM.60.10.3724-3731.1994","volume":"60","author":"A Varma","year":"1994","unstructured":"Varma A, Palsson B. Stoichiometric flux balance models quantitatively predict growth and metabolic by-product secretion in wild-type Escherichia coli W3110. Appl Environ Microbiol. 1994;60(10):3724\u201331.","journal-title":"Appl Environ Microbiol"},{"issue":"3","key":"408_CR35","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0006-3495(02)73903-9","volume":"83","author":"R Mahadevan","year":"2002","unstructured":"Mahadevan R, Edwards JS, Doyle FJ. Dynamic flux balance analysis of diauxic growth in Escherichia coli. Biophys J. 2002;83(3):1331\u201340.","journal-title":"Biophys J"},{"issue":"3","key":"408_CR36","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/bit.24748","volume":"110","author":"K H\u00f6ffner","year":"2013","unstructured":"H\u00f6ffner K, Harwood SM, Barton PI. A reliable simulator for dynamic flux balance analysis. Biotechnol Bioeng. 2013;110(3):792\u2013802.","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"408_CR37","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nprot.2009.203","volume":"5","author":"I Thiele","year":"2010","unstructured":"Thiele I, Palsson B\u00d8. A protocol for generating a high-quality genome-scale metabolic reconstruction. Nat Protoc. 2010;5(1):93\u2013121.","journal-title":"Nat Protoc"},{"key":"408_CR38","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9781139854610","volume-title":"Systems biology: constraint-based reconstruction and analysis","author":"BO Palsson","year":"2015","unstructured":"Palsson BO. Systems biology: constraint-based reconstruction and analysis. Cambridge: Cambridge University Press; 2015."},{"issue":"19","key":"408_CR39","doi-asserted-by":"crossref","first-page":"7797","DOI":"10.1073\/pnas.0702609104","volume":"104","author":"JH Park","year":"2007","unstructured":"Park JH, Lee KH, Kim TY, Lee SY. Metabolic engineering of Escherichia coli for the production of L-valine based on transcriptome analysis and in silico gene knockout simulation. Proc Natl Acad Sci U S A. 2007;104(19):7797\u2013802.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"408_CR40","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ymben.2009.07.001","volume":"11","author":"M a Asadollahi","year":"2009","unstructured":"Asadollahi M a, Maury J, Patil KR, Schalk M, Clark A, Nielsen J. Enhancing sesquiterpene production in Saccharomyces cerevisiae through in silico driven metabolic engineering. Metab Eng. 2009;11(6):328\u201334.","journal-title":"Metab Eng"},{"issue":"7","key":"408_CR41","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/biot.201000078","volume":"5","author":"SB Sohn","year":"2010","unstructured":"Sohn SB, Graf AB, Kim TY, Gasser B, Maurer M, Ferrer P, Mattanovich D, Lee SY. Genome-scale metabolic model of methylotrophic yeast Pichia pastoris and its use for in silico analysis of heterologous protein production. Biotechnol J. 2010;5(7):705\u201315.","journal-title":"Biotechnol J"},{"issue":"1","key":"408_CR42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1752-0509-6-24","volume":"6","author":"L Caspeta","year":"2012","unstructured":"Caspeta L, Shoaie S, Agren R, Nookaew I, Nielsen J. Genome-scale metabolic reconstructions of Pichia stipitis and Pichia pastoris and in silico evaluation of their potentials. BMC Syst Biol. 2012;6(1):24.","journal-title":"BMC Syst Biol"},{"issue":"50","key":"408_CR43","first-page":"2","volume":"9","author":"BKS Chung","year":"2010","unstructured":"Chung BKS, Selvarasu S, Camattari A, Ryu J, Lee H, Ahn J, Lee H, Lee D. Genome-scale metabolic reconstruction and in silico analysis of methylotrophic yeast Pichia pastoris for strain improvement. Microb Cell Fact. 2010;9(50):2\u201315.","journal-title":"Microb Cell Fact"},{"issue":"1","key":"408_CR44","doi-asserted-by":"crossref","first-page":"e0148031","DOI":"10.1371\/journal.pone.0148031","volume":"11","author":"M Tom\u00e0s-Gamisans","year":"2016","unstructured":"Tom\u00e0s-Gamisans M, Ferrer P, Albiol J. Integration and validation of the genome-scale metabolic models of Pichia pastoris: a comprehensive update of protein glycosylation pathways, lipid and energy metabolism. PLoS One. 2016;11(1):e0148031.","journal-title":"PLoS One"},{"issue":"5","key":"408_CR45","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1002\/bit.25863","volume":"113","author":"ZA Irani","year":"2015","unstructured":"Irani ZA, Kerkhoven EJ, Shojaosadati SA, Nielsen J. Genome-scale metabolic model of Pichia pastoris with native and humanized glycosylation of recombinant proteins. Biotechnol Bioeng. 2015;113(5):961\u20139.","journal-title":"Biotechnol Bioeng"},{"key":"408_CR46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ymben.2014.05.011","volume":"24","author":"J Nocon","year":"2014","unstructured":"Nocon J, Steiger MG, Pfeffer M, Sohn SB, Kim TY, Maurer M, Ru\u00dfmayer H, Pfl\u00fcgl S, Ask M, Haberhauer-Troyer C, Ortmayr K, Hann S, Koellensperger G, Gasser B, Lee SY, Mattanovich D. Model based engineering of Pichia pastoris central metabolism enhances recombinant protein production. Metab Eng. 2014;24:129\u201338.","journal-title":"Metab Eng"},{"issue":"11","key":"408_CR47","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nrm2030","volume":"7","author":"K Jaqaman","year":"2006","unstructured":"Jaqaman K, Danuser G. Linking data to models: data regression. Nat Rev Mol Cell Biol. 2006;7(11):813\u20139.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"408_CR48","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ymben.2014.07.004","volume":"25","author":"BJ S\u00e1nchez","year":"2014","unstructured":"S\u00e1nchez BJ, P\u00e9rez-Correa JR, Agosin E. Construction of robust dynamic genome-scale metabolic model structures of Saccharomyces cerevisiae through iterative re-parameterization. Metab Eng. 2014;25:159\u201373.","journal-title":"Metab Eng"},{"key":"408_CR49","volume-title":"Metabolic engineering principles and methodologies","author":"GM Stephanopoulos","year":"1998","unstructured":"Stephanopoulos GM, Aristidou AA, Nielsen J. Metabolic engineering principles and methodologies. San Diego: Academic; 1998."},{"issue":"2","key":"408_CR50","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1128\/AEM.55.2.468-477.1989","volume":"55","author":"E Postma","year":"1989","unstructured":"Postma E, Verduyn C, Scheffers W a, Van Dijken JP. Enzymic analysis of the crabtree effect in glucose-limited chemostat cultures of Saccharomyces cerevisiae. Appl Environ Microbiol. 1989;55(2):468\u201377.","journal-title":"Appl Environ Microbiol"},{"key":"408_CR51","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1371\/journal.pcbi.1002376","volume":"8","author":"X Feng","year":"2012","unstructured":"Feng X, Xu Y, Chen Y, Tang YJ. Integrating flux balance analysis into kinetic models to decipher the dynamic metabolism of shewanella oneidensis MR-1. PLoS Comput Biol. 2012;8:2.","journal-title":"PLoS Comput Biol"},{"issue":"6081","key":"408_CR52","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1126\/science.1216882","volume":"336","author":"R Schuetz","year":"2012","unstructured":"Schuetz R, Zamboni N, Zampieri M, Heinemann M, Sauer U. Multidimensional optimality of microbial metabolism. Science. 2012;336(6081):601\u20134.","journal-title":"Science"},{"issue":"14","key":"408_CR53","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1111\/j.1432-1033.2004.04213.x","volume":"271","author":"HG Holzh\u00fctter","year":"2004","unstructured":"Holzh\u00fctter HG. The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem. 2004;271(14):2905\u201322.","journal-title":"Eur J Biochem"},{"issue":"119","key":"408_CR54","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/msb4100162","volume":"3","author":"R Schuetz","year":"2007","unstructured":"Schuetz R, Kuepfer L, Sauer U. Systematic evaluation of objective functions for predicting intracellular fluxes in Escherichia coli. Mol Syst Biol. 2007;3(119):119.","journal-title":"Mol Syst Biol"},{"issue":"5","key":"408_CR55","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1016\/S0006-3495(02)75297-1","volume":"83","author":"ND Price","year":"2002","unstructured":"Price ND, Famili I, Beard D a, Palsson B\u00d8. Extreme pathways and Kirchhoff\u2019s second law. Biophys J. 2002;83(5):2879\u201382.","journal-title":"Biophys J"},{"key":"408_CR56","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.meteno.2016.05.002","volume":"3","author":"R Pereira","year":"2016","unstructured":"Pereira R, Nielsen J, Rocha I. Improving the flux distributions simulated with genome-scale metabolic models of Saccharomyces cerevisiae. Metab Eng Commun. 2016;3:153\u201363.","journal-title":"Metab Eng Commun"},{"issue":"1","key":"408_CR57","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/1752-0509-4-141","volume":"4","author":"K Baumann","year":"2010","unstructured":"Baumann K, Carnicer M, Dragosits M, Graf AB, Stadlmann J, Jouhten P, Maaheimo H, Gasser B, Albiol J, Mattanovich D, Ferrer P. A multi-level study of recombinant Pichia pastoris in different oxygen conditions. BMC Syst Biol. 2010;4(1):141.","journal-title":"BMC Syst Biol"},{"key":"408_CR58","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1021\/pr8007623","volume":"8","author":"M Dragosits","year":"2009","unstructured":"Dragosits M, Stadlmann J, Albiol J, Baumann K, Maurer M, Gasser B, Sauer M, Altmann F, Ferrer P, Mattanovich D, Cerdanyola B. The effect of temperature on the proteome of recombinant pichia pastoris research articles. J Proteome Res. 2009;8:1380\u201392.","journal-title":"J Proteome Res"},{"issue":"3","key":"408_CR59","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nprot.2007.99","volume":"2","author":"S Becker","year":"2007","unstructured":"Becker S, Feist AM, Mo ML, Hannum G, Palsson B\u00d8, Herrgard MJ. Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox. Nat Protoc. 2007;2(3):727\u201338.","journal-title":"Nat Protoc"},{"key":"408_CR60","doi-asserted-by":"crossref","unstructured":"Hyduke D, Schellenberger J, Que R, Fleming R, Thiele I, Orth J, Feist A, Zielinski D, Bordbar A, Lewis N, Rahmanian S, Kang J, Palsson B. COBRA Toolbox 2.0. Protoc Exch. 2011;[Online]. Available: http:\/\/www.nature.com\/protocolexchange\/protocols\/2097#\/related-articles .","DOI":"10.1038\/protex.2011.234"},{"issue":"6","key":"408_CR61","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1093\/bioinformatics\/btn051","volume":"24","author":"BJ Bornstein","year":"2008","unstructured":"Bornstein BJ, Keating SM, Jouraku A, Hucka M. LibSBML: an API library for SBML. Bioinformatics. 2008;24(6):880\u20131.","journal-title":"Bioinformatics"},{"issue":"10","key":"408_CR62","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1093\/bioinformatics\/btl111","volume":"22","author":"SM Keating","year":"2006","unstructured":"Keating SM, Bornstein BJ, Finney A, Hucka M. SBMLToolbox: an SBML toolbox for MATLAB users. Bioinformatics. 2006;22(10):1275\u20137.","journal-title":"Bioinformatics"},{"key":"408_CR63","first-page":"2399","volume":"135","author":"H Urk van","year":"1989","unstructured":"van Urk H, Postma E, Scheffers W a, van Dijken JP. Glucose transport in crabtree-positive and crabtree-negative yeasts. J Gen Microbiol. 1989;135:2399\u2013406.","journal-title":"J Gen Microbiol"},{"issue":"3","key":"408_CR64","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1109\/TLA.2014.6827863","volume":"12","author":"M C\u00e1rcamo","year":"2014","unstructured":"C\u00e1rcamo M, Saa PA, Torres J, Torres S, Mandujano P, Correa JRP, Agosin E. Effective dissolved oxygen control strategy for high-cell-density cultures. IEEE Lat Am Trans. 2014;12(3):389\u201394.","journal-title":"IEEE Lat Am Trans"},{"issue":"3","key":"408_CR65","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/bit.21451","volume":"98","author":"J Villadsen","year":"2007","unstructured":"Villadsen J, Patil KR. Optimal Fed-batch cultivation when mass transfer becomes limiting. Biotechnol Bioeng. 2007;98(3):706\u201310.","journal-title":"Biotechnol Bioeng"},{"key":"408_CR66","unstructured":"C\u00e1rcamo M. Producci\u00f3n de prote\u00ednas recombinantes en cultivos Fed-batch de Saccharomyces cerevisiae y Escherichia coli. Santiago: Pontificia Unversidad Cat\u00f3lica de Chile; 2013."},{"issue":"2","key":"408_CR67","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1038\/nprot.2006.126","volume":"1","author":"B Tolner","year":"2006","unstructured":"Tolner B, Smith L, Begent RHJ, Chester K a. Production of recombinant protein in Pichia pastoris by fermentation. Nat Protoc. 2006;1(2):1006\u201321.","journal-title":"Nat Protoc"},{"issue":"8","key":"408_CR68","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1111\/j.1567-1364.2009.00561.x","volume":"9","author":"H Marx","year":"2009","unstructured":"Marx H, Mecklenbr\u00e4uker A, Gasser B, Sauer M, Mattanovich D. Directed gene copy number amplification in Pichia pastoris by vector integration into the ribosomal DNA locus. FEMS Yeast Res. 2009;9(8):1260\u201370.","journal-title":"FEMS Yeast Res"},{"issue":"9","key":"408_CR69","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1021\/ie801717t","volume":"48","author":"J Egea","year":"2009","unstructured":"Egea J, Balsa-Canto E. Dynamic optimization of nonlinear processes with an enhanced scatter search method. Ind Eng Chem Res. 2009;48(9):4388\u2013401.","journal-title":"Ind Eng Chem Res"},{"issue":"2","key":"408_CR70","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jfoodeng.2007.02.006","volume":"82","author":"E Balsa-Canto","year":"2007","unstructured":"Balsa-Canto E, Rodriguez-Fernandez M, Banga JR. Optimal design of dynamic experiments for improved estimation of kinetic parameters of thermal degradation. J Food Eng. 2007;82(2):178\u201388.","journal-title":"J Food Eng"},{"key":"408_CR71","first-page":"5","volume":"14","author":"J Sacher","year":"2011","unstructured":"Sacher J, Saa P, C\u00e1rcamo M, L\u00f3pez J, Gelmi C a, P\u00e9rez-Correa R. Improved calibration of a solid substrate fermentation model. Electron J Biotechnol. 2011;14:5.","journal-title":"Electron J Biotechnol"},{"key":"408_CR72","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1371\/journal.pcbi.1002379","volume":"8","author":"K Sriram","year":"2012","unstructured":"Sriram K, Rodriguez-Fernandez M, Doyle FJ. Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post-traumatic stress disorder (PTSD) in humans. PLoS Comput Biol. 2012;8:2.","journal-title":"PLoS Comput Biol"},{"issue":"7","key":"408_CR73","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2166\/wst.2001.0444","volume":"43","author":"B Petersen","year":"2001","unstructured":"Petersen B, Gernaey K, Vanrolleghem PA. Practical identifiability of model parameters by combined respirometric-titrimetric measurements. Water Sci Technol. 2001;43(7):347\u201355.","journal-title":"Water Sci Technol"},{"key":"408_CR74","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1152\/ajpregu.1984.246.5.R665","volume":"246","author":"EM Landaw","year":"1984","unstructured":"Landaw EM, DiStefano 3rd JJ. Multiexponential, multicompartmental, and noncompartmental modeling. II. Data analysis and statistical considerations. Am J Physiol Regul Integr Comp Physiol. 1984;246:5.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"48","key":"408_CR75","doi-asserted-by":"crossref","first-page":"18514","DOI":"10.1021\/ie501298b","volume":"53","author":"BJ S\u00e1nchez","year":"2014","unstructured":"S\u00e1nchez BJ, Soto DC, Jorquera H, Gelmi CA, P\u00e9rez-Correa JR. HIPPO: An iterative reparametrization method for identification and calibration of dynamic bioreactor models of complex processes. Ind Eng Chem Res. 2014;53(48):18514\u201325.","journal-title":"Ind Eng Chem Res"},{"issue":"347","key":"408_CR76","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1080\/01621459.1974.10480196","volume":"69","author":"MA Stephens","year":"1974","unstructured":"Stephens MA. EDF statistics for goodness of fit and some comparisons. J Am Stat Assoc. 1974;69(347):730\u20137.","journal-title":"J Am Stat Assoc"},{"issue":"23","key":"408_CR77","doi-asserted-by":"crossref","first-page":"15112","DOI":"10.1073\/pnas.232349399","volume":"99","author":"D Segr\u00e8","year":"2002","unstructured":"Segr\u00e8 D, Vitkup D, Church GM. Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci U S A. 2002;99(23):15112\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"408_CR78","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1002\/biot.201300334","volume":"9","author":"C Rebnegger","year":"2014","unstructured":"Rebnegger C, Graf AB, Valli M, Steiger MG, Gasser B, Maurer M, Mattanovich D. In Pichia pastoris, growth rate regulates protein synthesis and secretion, mating and stress response. Biotechnol J. 2014;9(4):511\u201325.","journal-title":"Biotechnol J"},{"issue":"1","key":"408_CR79","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1574-6976.1997.tb00346.x","volume":"21","author":"E Boles","year":"1997","unstructured":"Boles E, Hollenberg CP. The molecular genetics of hexose transport in yeasts. FEMS Microbiol Rev. 1997;21(1):85\u2013111.","journal-title":"FEMS Microbiol Rev"},{"issue":"8","key":"408_CR80","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1007\/s00253-013-5501-x","volume":"98","author":"H Cheng","year":"2014","unstructured":"Cheng H, Lv J, Wang H, Wang B, Li Z, Deng Z. Genetically engineered Pichia pastoris yeast for conversion of glucose to xylitol by a single-fermentation process. Appl Microbiol Biotechnol. 2014;98(8):3539\u201352.","journal-title":"Appl Microbiol Biotechnol"},{"issue":"3","key":"408_CR81","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1113\/jphysiol.1926.sp002296","volume":"61","author":"EB Verney","year":"1926","unstructured":"Verney EB. The osmotic pressure of the proteins of human serum and plasma. J Physiol. 1926;61(3):319\u201328.","journal-title":"J Physiol"},{"issue":"6","key":"408_CR82","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s00239-008-9162-9","volume":"67","author":"DW Raiford","year":"2008","unstructured":"Raiford DW, Heizer EM, Miller RV, Akashi H, Raymer ML, Krane DE. Do amino acid biosynthetic costs constrain protein evolution in Saccharomyces cerevisiae? J Mol Evol. 2008;67(6):621\u201330.","journal-title":"J Mol Evol"},{"issue":"9","key":"408_CR83","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1021\/bi952713d","volume":"35","author":"MG West","year":"1996","unstructured":"West MG, Horne DW, Appling DR. Metabolic role of cytoplasmic isozymes of 5,10-methylenetetrahydrofolate dehydrogenase in Saccharomyces cerevisiae. Biochemistry. 1996;35(9):3122\u201332.","journal-title":"Biochemistry"},{"issue":"3","key":"408_CR84","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1385\/MB:31:3:245","volume":"31","author":"D Porro","year":"2005","unstructured":"Porro D, Sauer M, Branduardi P, Mattanovich D. Recombinant protein production in yeasts. Mol Biotechnol. 2005;31(3):245\u201359.","journal-title":"Mol Biotechnol"},{"issue":"1","key":"408_CR85","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12918-014-0142-y","volume":"8","author":"Y Morales","year":"2014","unstructured":"Morales Y, Tortajada M, Pic\u00f3 J, Veh\u00ed J, Llaneras F. Validation of an FBA model for Pichia pastoris in chemostat cultures. BMC Syst Biol. 2014;8(1):142.","journal-title":"BMC Syst Biol"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12918-017-0408-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T19:49:28Z","timestamp":1601668168000},"score":1,"resource":{"primary":{"URL":"http:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/s12918-017-0408-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,21]]},"references-count":85,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["408"],"URL":"https:\/\/doi.org\/10.1186\/s12918-017-0408-2","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,21]]},"article-number":"27"}}