{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T01:02:16Z","timestamp":1774400536375,"version":"3.50.1"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>The identification of genetic target genes is a key step for rational engineering of production strains towards bio-based chemicals, fuels or therapeutics. This is often a difficult task, because superior production performance typically requires a combination of multiple targets, whereby the complex metabolic networks complicate straightforward identification. Recent attempts towards target prediction mainly focus on the prediction of gene deletion targets and therefore can cover only a part of genetic modifications proven valuable in metabolic engineering. Efficient in silico methods for simultaneous genome-scale identification of targets to be amplified or deleted are still lacking.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Here we propose the identification of targets via flux correlation to a chosen objective flux as approach towards improved biotechnological production strains with optimally designed fluxes. The approach, we name Flux Design, computes elementary modes and, by search through the modes, identifies targets to be amplified (positive correlation) or down-regulated (negative correlation). Supported by statistical evaluation, a target potential is attributed to the identified reactions in a quantitative manner. Based on systems-wide models of the industrial microorganisms <jats:italic>Corynebacterium glutamicum<\/jats:italic> and <jats:italic>Aspergillus niger<\/jats:italic>, up to more than 20,000 modes were obtained for each case, differing strongly in production performance and intracellular fluxes. For lysine production in <jats:italic>C. glutamicum<\/jats:italic> the identified targets nicely matched with reported successful metabolic engineering strategies. In addition, simulations revealed insights, e.g. into the flexibility of energy metabolism. For enzyme production in <jats:italic>A.niger<\/jats:italic> flux correlation analysis suggested a number of targets, including non-obvious ones. Hereby, the relevance of most targets depended on the metabolic state of the cell and also on the carbon source.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Objective flux correlation analysis provided a detailed insight into the metabolic networks of industrially relevant prokaryotic and eukaryotic microorganisms. It was shown that capacity, pathway usage, and relevant genetic targets for optimal production partly depend on the network structure and the metabolic state of the cell which should be considered in future metabolic engineering strategies. The presented strategy can be generally used to identify priority sorted amplification and deletion targets for metabolic engineering purposes under various conditions and thus displays a useful strategy to be incorporated into efficient strain and bioprocess optimization.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-3-120","type":"journal-article","created":{"date-parts":[[2009,12,25]],"date-time":"2009-12-25T19:14:22Z","timestamp":1261768462000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Flux Design: In silico design of cell factories based on correlation of pathway fluxes to desired properties"],"prefix":"10.1186","volume":"3","author":[{"given":"Guido","family":"Melzer","sequence":"first","affiliation":[]},{"given":"Manely Eslahpazir","family":"Esfandabadi","sequence":"additional","affiliation":[]},{"given":"Ezequiel","family":"Franco-Lara","sequence":"additional","affiliation":[]},{"given":"Christoph","family":"Wittmann","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,12,25]]},"reference":[{"issue":"2","key":"388_CR1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1039\/B712395G","volume":"4","author":"HU Kim","year":"2008","unstructured":"Kim HU, Kim TY, Lee SY: Metabolic flux analysis and metabolic engineering of microorganisms. Mol Biosyst. 2008, 4 (2): 113-120. 10.1039\/b712395g","journal-title":"Mol Biosyst"},{"issue":"5-6","key":"388_CR2","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.ymben.2007.05.005","volume":"9","author":"PF Suthers","year":"2007","unstructured":"Suthers PF, Burgard AP, Dasika MS, Nowroozi F, Van Dien S, Keasling JD, Maranas CD: Metabolic flux elucidation for large-scale models using 13C labeled isotopes. Metab Eng. 2007, 9 (5-6): 387-405. 10.1016\/j.ymben.2007.05.005","journal-title":"Metab Eng"},{"key":"388_CR3","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1186\/1471-2105-6-308","volume":"6","author":"KR Patil","year":"2005","unstructured":"Patil KR, Rocha I, Forster J, Nielsen J: Evolutionary programming as a platform for in silico metabolic engineering. BMC Bioinformatics. 2005, 6: 308- 10.1186\/1471-2105-6-308","journal-title":"BMC Bioinformatics"},{"issue":"23","key":"388_CR4","doi-asserted-by":"publisher","first-page":"15112","DOI":"10.1073\/pnas.232349399","volume":"99","author":"D Segre","year":"2002","unstructured":"Segre D, Vitkup D, Church GM: Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci USA. 2002, 99 (23): 15112-15117. 10.1073\/pnas.232349399","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"388_CR5","doi-asserted-by":"publisher","first-page":"3634","DOI":"10.1128\/AEM.02708-07","volume":"74","author":"CT Trinh","year":"2008","unstructured":"Trinh CT, Unrean P, Srienc F: Minimal Escherichia coli cell for the most efficient production of ethanol from hexoses and pentoses. Appl Environ Microbiol. 2008, 74 (12): 3634-3643. 10.1128\/AEM.02708-07","journal-title":"Appl Environ Microbiol"},{"key":"388_CR6","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1475-2859-6-6","volume":"6","author":"C Wittmann","year":"2007","unstructured":"Wittmann C: Fluxome analysis using GC-MS. Microb Cell Fact. 2007, 6: 6- 10.1186\/1475-2859-6-6","journal-title":"Microb Cell Fact"},{"issue":"1","key":"388_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ymben.2005.08.003","volume":"8","author":"P Pharkya","year":"2006","unstructured":"Pharkya P, Maranas CD: An optimization framework for identifying reaction activation\/inhibition or elimination candidates for overproduction in microbial systems. Metab Eng. 2006, 8 (1): 1-13. 10.1016\/j.ymben.2005.08.003","journal-title":"Metab Eng"},{"issue":"2","key":"388_CR8","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.jbiotec.2007.05.026","volume":"132","author":"J Becker","year":"2007","unstructured":"Becker J, Klopprogge C, Herold A, Zelder O, Bolten CJ, Wittmann C: Metabolic flux engineering of L-lysine production in Corynebacterium glutamicum--over expression and modification of G6P dehydrogenase. J Biotechnol. 2007, 132 (2): 99-109. 10.1016\/j.jbiotec.2007.05.026","journal-title":"J Biotechnol"},{"issue":"12","key":"388_CR9","doi-asserted-by":"publisher","first-page":"8587","DOI":"10.1128\/AEM.71.12.8587-8596.2005","volume":"71","author":"J Becker","year":"2005","unstructured":"Becker J, Klopprogge C, Zelder O, Heinzle E, Wittmann C: Amplified expression of fructose 1, 6-bisphosphatase in Corynebacterium glutamicum increases in vivo flux through the pentose phosphate pathway and lysine production on different carbon sources. Appl Environ Microbiol. 2005, 71 (12): 8587-8596. 10.1128\/AEM.71.12.8587-8596.2005","journal-title":"Appl Environ Microbiol"},{"issue":"6","key":"388_CR10","doi-asserted-by":"publisher","first-page":"3750","DOI":"10.1529\/biophysj.104.048090","volume":"87","author":"L Wang","year":"2004","unstructured":"Wang L, Birol I, Hatzimanikatis V: Metabolic control analysis under uncertainty: framework development and case studies. Biophys J. 2004, 87 (6): 3750-3763. 10.1529\/biophysj.104.048090","journal-title":"Biophys J"},{"issue":"5","key":"388_CR11","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s00253-008-1770-1","volume":"81","author":"CT Trinh","year":"2009","unstructured":"Trinh CT, Wlaschin A, Srienc F: Elementary mode analysis: a useful metabolic pathway analysis tool for characterizing cellular metabolism. Appl Microbiol Biotechnol. 2009, 81 (5): 813-826. 10.1007\/s00253-008-1770-1","journal-title":"Appl Microbiol Biotechnol"},{"issue":"4","key":"388_CR12","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.ymben.2006.02.001","volume":"8","author":"JO Kr\u00f6mer","year":"2006","unstructured":"Kr\u00f6mer JO, Wittmann C, Schr\u00f6der H, Heinzle E: Metabolic pathway analysis for rational design of L-methionine production by Escherichia coli and Corynebacterium glutamicum. Metab Eng. 2006, 8 (4): 353-369. 10.1016\/j.ymben.2006.02.001","journal-title":"Metab Eng"},{"issue":"2","key":"388_CR13","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/bit.10305","volume":"79","author":"R Carlson","year":"2002","unstructured":"Carlson R, Fell D, Srienc F: Metabolic pathway analysis of a recombinant yeast for rational strain development. Biotechnol Bioeng. 2002, 79 (2): 121-134. 10.1002\/bit.10305","journal-title":"Biotechnol Bioeng"},{"key":"388_CR14","doi-asserted-by":"publisher","first-page":"e26","DOI":"10.1371\/journal.pcbi.0040026","volume":"4","author":"RA Notebaart","year":"2008","unstructured":"Notebaart RA, B T, Siezen RJ, Papp B: Co-Regulation of Metabolic Genes Is Better Explained by Flux Coupling Than by Network Distance. PLoS Comput Biol. 2008, 4: e26- 10.1371\/journal.pcbi.0040026","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"388_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00253-005-0155-y","volume":"69","author":"W Leuchtenberger","year":"2005","unstructured":"Leuchtenberger W, Huthmacher K, Drauz K: Biotechnological production of amino acids and derivatives: current status and prospects. Appl Microbiol Biotechnol. 2005, 69 (1): 1-8. 10.1007\/s00253-005-0155-y","journal-title":"Appl Microbiol Biotechnol"},{"key":"388_CR16","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1002\/bit.22067","volume":"102","author":"KR Kjeldsen","year":"2008","unstructured":"Kjeldsen KR, Nielsen J: In silico genome-scale reconstruction and validation of the Corynebacterium glutamicum metabolic network. Biotechnol Bioeng. 2008, 102: 583-597. 10.1002\/bit.22067.","journal-title":"Biotechnol Bioeng"},{"key":"388_CR17","volume-title":"Microbiology Monographs","author":"C Wittmann","year":"2007","unstructured":"Wittmann C, Becker J: The L-lysine story: From metabolic pathways to industrial production. Microbiology Monographs. 2007, Springer Berlin\/Heidelberg"},{"issue":"Pt 1","key":"388_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1099\/mic.0.2006\/001479-0","volume":"153","author":"MG Jones","year":"2007","unstructured":"Jones MG: The first filamentous fungal genome sequences: Aspergillus leads the way for essential everyday resources or dusty museum specimens?. Microbiology. 2007, 153 (Pt 1): 1-6. 10.1099\/mic.0.2006\/001479-0","journal-title":"Microbiology"},{"key":"388_CR19","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/msb.2008.12","volume":"4","author":"MR Andersen","year":"2008","unstructured":"Andersen MR, Nielsen ML, Nielsen J: Metabolic model integration of the bibliome, genome, metabolome and reactome of Aspergillus niger. Mol Syst Biol. 2008, 4: 178- 10.1038\/msb.2008.12","journal-title":"Mol Syst Biol"},{"issue":"1","key":"388_CR20","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/cbic.200700486","volume":"9","author":"A Zuccaro","year":"2008","unstructured":"Zuccaro A, Gotze S, Kneip S, Dersch P, Seibel J: Tailor-made fructooligosaccharides by a combination of substrate and genetic engineering. Chembiochem. 2008, 9 (1): 143-149. 10.1002\/cbic.200700486","journal-title":"Chembiochem"},{"issue":"1","key":"388_CR21","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1006\/mben.1999.0136","volume":"2","author":"H Pedersen","year":"2000","unstructured":"Pedersen H, Christensen B, Hjort C, Nielsen J: Construction and characterization of an oxalic acid nonproducing strain of Aspergillus niger. Metab Eng. 2000, 2 (1): 34-41. 10.1006\/mben.1999.0136","journal-title":"Metab Eng"},{"issue":"5","key":"388_CR22","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1002\/biot.200900034","volume":"4","author":"A Naundorf","year":"2009","unstructured":"Naundorf A, Melzer G, Archelas A, Furstoss R, Wohlgemuth R: Influence of pH on the expression of a recombinant epoxide hydrolase in Aspergillus niger. Biotechnol J. 2009, 4 (5): 756-765. 10.1002\/biot.200900034","journal-title":"Biotechnol J"},{"key":"388_CR23","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1142\/S0218339094000131","volume":"2","author":"S Schuster","year":"1994","unstructured":"Schuster S, Hilgetag C: On elementary flux modes in biochemical reaction systems at steady state. Journal of Biological Systems. 1994, 2: 165-182. 10.1142\/S0218339094000131.","journal-title":"Journal of Biological Systems"},{"issue":"2","key":"388_CR24","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0167-7799(98)01290-6","volume":"17","author":"S Schuster","year":"1999","unstructured":"Schuster S, Dandekar T, Fell DA: Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering. Trends Biotechnol. 1999, 17 (2): 53-60. 10.1016\/S0167-7799(98)01290-6","journal-title":"Trends Biotechnol"},{"issue":"7","key":"388_CR25","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1021\/jp034523f","volume":"108","author":"C Wagner","year":"2004","unstructured":"Wagner C: Nullspace approach to determine the elementary modes of chemical reaction systems. Journal of Physical Chemistry B. 2004, 108 (7): 2425-2431. 10.1021\/jp034523f.","journal-title":"Journal of Physical Chemistry B"},{"issue":"19","key":"388_CR26","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1093\/bioinformatics\/btn401","volume":"24","author":"M Terzer","year":"2008","unstructured":"Terzer M, Stelling J: Large-scale computation of elementary flux modes with bit pattern trees. Bioinformatics. 2008, 24 (19): 2229-2235. 10.1093\/bioinformatics\/btn401","journal-title":"Bioinformatics"},{"issue":"15","key":"388_CR27","doi-asserted-by":"publisher","first-page":"9697","DOI":"10.1073\/pnas.112318199","volume":"99","author":"JA Bernstein","year":"2002","unstructured":"Bernstein JA, Khodursky AB, Lin PH, Lin-Chao S, Cohen SN: Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays. Proc Natl Acad Sci USA. 2002, 99 (15): 9697-9702. 10.1073\/pnas.112318199","journal-title":"Proc Natl Acad Sci USA"},{"issue":"9","key":"388_CR28","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/nmeth.1239","volume":"5","author":"G Butland","year":"2008","unstructured":"Butland G, Babu M, Diaz-Mejia JJ, Bohdana F, Phanse S, Gold B, Yang W, Li J, Gagarinova AG, Pogoutse O, et al.: eSGA: E. coli synthetic genetic array analysis. Nat Methods. 2008, 5 (9): 789-795. 10.1038\/nmeth.1239","journal-title":"Nat Methods"},{"key":"388_CR29","first-page":"277","volume-title":"Handbook of Corynebacterium glutamicum","author":"C Wittmann","year":"2005","unstructured":"Wittmann C, de Graaf A: Metabolic flux analysis in Corynebacterium glutamicum. Handbook of Corynebacterium glutamicum. Edited by: Eggeling L, Bott M. 2005, 277-304. Boca Raton: CRC Press,"},{"issue":"21","key":"388_CR30","doi-asserted-by":"publisher","first-page":"4243","DOI":"10.1046\/j.1432-1033.2003.03798.x","volume":"270","author":"H David","year":"2003","unstructured":"David H, \u00c5kesson M, Nielsen J: Reconstruction of the central carbon metabolism of Aspergillus niger. European Journal of Biochemistry. 2003, 270 (21): 4243-4253. 10.1046\/j.1432-1033.2003.03798.x","journal-title":"European Journal of Biochemistry"},{"key":"388_CR31","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/1471-2105-5-112","volume":"5","author":"J Sun","year":"2004","unstructured":"Sun J, Zeng AP: IdentiCS--identification of coding sequence and in silico reconstruction of the metabolic network directly from unannotated low-coverage bacterial genome sequence. BMC Bioinformatics. 2004, 5: 112- 10.1186\/1471-2105-5-112","journal-title":"BMC Bioinformatics"},{"issue":"8","key":"388_CR32","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1093\/glycob\/cwn044","volume":"18","author":"N Deshpande","year":"2008","unstructured":"Deshpande N, Wilkins MR, Packer N, Nevalainen H: Protein glycosylation pathways in filamentous fungi. Glycobiology. 2008, 18 (8): 626-637. 10.1093\/glycob\/cwn044","journal-title":"Glycobiology"},{"key":"388_CR33","first-page":"109","volume-title":"The Role of Protein and Amino Acids in Sustaining and Enhancing Performance","author":"DM Bier","year":"1999","unstructured":"Bier DM: The energy costs of protein metabolism: lean and mean on Uncle Sam's team. The Role of Protein and Amino Acids in Sustaining and Enhancing Performance. 1999, 109-119. Washington, DC: National Academy Press"},{"issue":"1","key":"388_CR34","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/S0304-4165(99)00165-8","volume":"1473","author":"R Apweiler","year":"1999","unstructured":"Apweiler R, Hermjakob H, Sharon N: On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999, 1473 (1): 4-8.","journal-title":"Biochim Biophys Acta"},{"issue":"21","key":"388_CR35","doi-asserted-by":"crossref","first-page":"9815","DOI":"10.1016\/S0021-9258(18)67588-X","volume":"261","author":"RB Trimble","year":"1986","unstructured":"Trimble RB, Atkinson PH: Structure of yeast external invertase Man8-14GlcNAc processing intermediates by 500-megahertz 1H NMR spectroscopy. J Biol Chem. 1986, 261 (21): 9815-9824.","journal-title":"J Biol Chem"},{"issue":"2","key":"388_CR36","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/nbt1282","volume":"25","author":"HJ Pel","year":"2007","unstructured":"Pel HJ, de Winde JH, Archer DB, Dyer PS, Hofmann G, Schaap PJ, Turner G, de Vries RP, Albang R, Albermann K, et al.: Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88. Nat Biotechnol. 2007, 25 (2): 221-231. 10.1038\/nbt1282","journal-title":"Nat Biotechnol"},{"key":"388_CR37","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1042\/bj2820423","volume":"282","author":"G Williamson","year":"1992","unstructured":"Williamson G, Belshaw JP, Williamson MP: O-glycosylation in Aspergillus glucoamylase. Conformation and role in binding. Biochem. 1992, 282: 423-428.","journal-title":"Biochem"},{"issue":"4","key":"388_CR38","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1021\/bp034020r","volume":"19","author":"W Prathumpai","year":"2003","unstructured":"Prathumpai W, Gabelgaard JB, Wanchanthuek P, Vondervoort van de PJ, de Groot MJ, McIntyre M, Nielsen J: Metabolic control analysis of xylose catabolism in Aspergillus. Biotechnol Prog. 2003, 19 (4): 1136-1141. 10.1021\/bp034020r","journal-title":"Biotechnol Prog"},{"issue":"8","key":"388_CR39","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.tibtech.2004.06.010","volume":"22","author":"JA Papin","year":"2004","unstructured":"Papin JA, Stelling J, Price ND, Klamt S, Schuster S, Palsson BO: Comparison of network-based pathway analysis methods. Trends Biotechnol. 2004, 22 (8): 400-405. 10.1016\/j.tibtech.2004.06.010","journal-title":"Trends Biotechnol"},{"issue":"2","key":"388_CR40","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s002850200143","volume":"45","author":"S Schuster","year":"2002","unstructured":"Schuster S, Hilgetag C, Woods JH, Fell DA: Reaction routes in biochemical reaction systems: algebraic properties, validated calculation procedure and example from nucleotide metabolism. J Math Biol. 2002, 45 (2): 153-181. 10.1007\/s002850200143","journal-title":"J Math Biol"},{"issue":"2","key":"388_CR41","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.femsle.2004.11.014","volume":"242","author":"J Ohnishi","year":"2005","unstructured":"Ohnishi J, Katahira R, Mitsuhashi S, Kakita S, Ikeda M: A novel gnd mutation leading to increased L-lysine production in Corynebacterium glutamicum. FEMS Microbiol Lett. 2005, 242 (2): 265-274. 10.1016\/j.femsle.2004.11.014","journal-title":"FEMS Microbiol Lett"},{"issue":"1","key":"388_CR42","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s002530051132","volume":"49","author":"L Eggeling","year":"1998","unstructured":"Eggeling L, Oberle S, Sahm H: Improved L-lysine yield with Corynebacterium glutamicum: use of dapA resulting in increased flux combined with growth limitation. Appl Microbiol Biotechnol. 1998, 49 (1): 24-30. 10.1007\/s002530051132","journal-title":"Appl Microbiol Biotechnol"},{"issue":"1","key":"388_CR43","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1128\/aem.59.1.316-321.1993","volume":"59","author":"S Broer","year":"1993","unstructured":"Broer S, Eggeling L, Kramer R: Strains of Corynebacterium glutamicum with Different Lysine Productivities May Have Different Lysine Excretion Systems. Appl Environ Microbiol. 1993, 59 (1): 316-321.","journal-title":"Appl Environ Microbiol"},{"issue":"1-3","key":"388_CR44","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/S0168-1656(03)00153-6","volume":"104","author":"A Marx","year":"2003","unstructured":"Marx A, Hans S, Mockel B, Bathe B, de Graaf AA: Metabolic phenotype of phosphoglucose isomerase mutants of Corynebacterium glutamicum. J Biotechnol. 2003, 104 (1-3): 185-197. 10.1016\/S0168-1656(03)00153-6","journal-title":"J Biotechnol"},{"issue":"3","key":"388_CR45","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1007\/s00253-007-0904-1","volume":"76","author":"B Blombach","year":"2007","unstructured":"Blombach B, Schreiner ME, Moch M, Oldiges M, Eikmanns BJ: Effect of pyruvate dehydrogenase complex deficiency on L-lysine production with Corynebacterium glutamicum. Appl Microbiol Biotechnol. 2007, 76 (3): 615-623. 10.1007\/s00253-007-0904-1","journal-title":"Appl Microbiol Biotechnol"},{"issue":"Suppl 1 (1)","key":"388_CR46","first-page":"S141","volume":"46","author":"DI Jacobs","year":"2008","unstructured":"Jacobs DI, Olsthoorn MM, Maillet I, Akeroyd M, Breestraat S, Donkers S, Hoeven van der RA, Hondel van den CA, Kooistra R, Lapointe T, et al.: Effective lead selection for improved protein production in Aspergillus niger based on integrated genomics. Fungal Genet Biol. 2008, 46 (Suppl 1 (1)): S141-152.","journal-title":"Fungal Genet Biol"},{"issue":"2","key":"388_CR47","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.jbiotec.2006.02.024","volume":"125","author":"HJ van den Brink","year":"2006","unstructured":"Brink van den HJ, Petersen SG, Rahbek-Nielsen H, Hellmuth K, Harboe M: Increased production of chymosin by glycosylation. J Biotechnol. 2006, 125 (2): 304-310. 10.1016\/j.jbiotec.2006.02.024","journal-title":"J Biotechnol"},{"issue":"3","key":"388_CR48","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1128\/AEM.65.3.1168-1174.1999","volume":"65","author":"FJ Moralejo","year":"1999","unstructured":"Moralejo FJ, Cardoza RE, Gutierrez S, Martin JF: Thaumatin production in Aspergillus awamori by use of expression cassettes with strong fungal promoters and high gene dosage. Appl Environ Microbiol. 1999, 65 (3): 1168-1174.","journal-title":"Appl Environ Microbiol"},{"issue":"4","key":"388_CR49","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.jbiotec.2007.08.034","volume":"132","author":"G Melzer","year":"2007","unstructured":"Melzer G, Dalpiaz A, Grote A, Kucklick M, G\u00f6cke Y, Jonas R, Dersch P, Franco-Lara E, N\u00f6rtemann B, Hempel DC: Metabolic flux analysis using stoichiometric models for Aspergillus niger: comparison under glucoamylase-producing and non-producing conditions. J Biotechnol. 2007, 132 (4): 405-417. 10.1016\/j.jbiotec.2007.08.034","journal-title":"J Biotechnol"},{"issue":"2","key":"388_CR50","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1006\/mben.1999.0114","volume":"1","author":"K Schmidt","year":"1999","unstructured":"Schmidt K, Norregaard LC, Pedersen B, Meissner A, Duus JO, Nielsen JO, Villadsen J: Quantification of intracellular metabolic fluxes from fractional enrichment and 13C-13C coupling constraints on the isotopomer distribution in labeled biomass components. Metab Eng. 1999, 1 (2): 166-179. 10.1006\/mben.1999.0114","journal-title":"Metab Eng"},{"issue":"4","key":"388_CR51","first-page":"573","volume":"3","author":"C Riedel","year":"2001","unstructured":"Riedel C, Rittmann D, Dangel P, Mockel B, Petersen S, Sahm H, Eikmanns BJ: Characterization of the phosphoenolpyruvate carboxykinase gene from Corynebacterium glutamicum and significance of the enzyme for growth and amino acid production. J Mol Microbiol Biotechnol. 2001, 3 (4): 573-583.","journal-title":"J Mol Microbiol Biotechnol"},{"issue":"9","key":"388_CR52","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1128\/aem.59.9.2927-2937.1993","volume":"59","author":"DA Mills","year":"1993","unstructured":"Mills DA, Flickinger MC: Cloning and sequence analysis of the meso-diaminopimelate decarboxylase gene from Bacillus methanolicus MGA3 and comparison to other decarboxylase genes. Appl Environ Microbiol. 1993, 59 (9): 2927-2937.","journal-title":"Appl Environ Microbiol"},{"issue":"6","key":"388_CR53","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1021\/bp00024a001","volume":"9","author":"MC Flickinger","year":"1993","unstructured":"Flickinger MC, Rouse MP: Sustaining protein synthesis in the absence of rapid cell division: an investigation of plasmid-encoded protein expression in Escherichia coli during very slow growth. Biotechnol Prog. 1993, 9 (6): 555-572. 10.1021\/bp00024a001","journal-title":"Biotechnol Prog"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-3-120.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T03:19:34Z","timestamp":1630466374000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-3-120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":53,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["388"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-3-120","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12]]},"assertion":[{"value":"4 June 2009","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 December 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 December 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"120"}}