{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:43:35Z","timestamp":1790545415606,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,8,6]],"date-time":"2015-08-06T00:00:00Z","timestamp":1438819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biotechnology Progress"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:p>\n                    <jats:sup>13<\/jats:sup>\n                    C\u2010metabolic flux analysis was used to understand copper deficiency\u2010related restructuring of energy metabolism, which leads to excessive lactate production in recombinant protein\u2010producing CHO cells. Stationary\u2010phase labeling experiments with U\u2010\n                    <jats:sup>13<\/jats:sup>\n                    C glucose were conducted on CHO cells grown under high and limiting copper in 3 L fed\u2010batch bioreactors. The resultant labeling patterns of soluble metabolites were measured by GC\u2010MS and used to estimate metabolic fluxes in the central carbon metabolism pathways using OpenFlux. Fluxes were evaluated 300 times from stoichiometrically feasible random guess values and their confidence intervals calculated by Monte Carlo simulations. Results from metabolic flux analysis exhibited significant carbon redistribution throughout the metabolic network in cells under Cu deficiency. Specifically, glycolytic fluxes increased (25%\u201379% relative to glucose uptake) whereas fluxes through the TCA and pentose phosphate pathway (PPP) were lower (15%\u201323% and 74%, respectively) compared with the Cu\u2010containing condition. Furthermore, under Cu deficiency, 33% of the flux entering TCA via the pyruvate node was redirected to lactate and malate production. Based on these results, we hypothesize that Cu deficiency disrupts the electron transport chain causing ATP deficiency, redox imbalance, and oxidative stress, which in turn drive copper\u2010deficient CHO cells to produce energy via aerobic glycolysis, which is associated with excessive lactate production, rather than the more efficient route of oxidative phosphorylation. \u00a9 2015 American Institute of Chemical Engineers\n                    <jats:italic>Biotechnol. Prog.<\/jats:italic>\n                    , 31:1179\u20131186, 2015\n                  <\/jats:p>","DOI":"10.1002\/btpr.2131","type":"journal-article","created":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T02:43:41Z","timestamp":1434941021000},"page":"1179-1186","source":"Crossref","is-referenced-by-count":48,"title":["Elucidating the role of copper in CHO cell energy metabolism using\n                    <sup>13<\/sup>\n                    C metabolic flux analysis"],"prefix":"10.1002","volume":"31","author":[{"given":"Shilpa","family":"Nargund","sequence":"first","affiliation":[{"name":"Drug Substance Technologies, Process Development Amgen Inc., One Amgen Center Drive Thousand Oaks CA 91320"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Attribute Sciences, Process Development, Amgen Inc., One Amgen Center Drive Thousand Oaks CA 91320"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan T.","family":"Goudar","sequence":"additional","affiliation":[{"name":"Drug Substance Technologies, Process Development Amgen Inc., One Amgen Center Drive Thousand Oaks CA 91320"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,8,6]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"Cell Culture Technology for Pharmaceutical and Cell\u2010Based Therapies","author":"Ozturk S","year":"2006"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.23200"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","unstructured":"AltamiranoC BerriosJ VergaraM BecerraS.Advances in improving mammalian cells metabolism for recombinant protein production.Electron J Biotechnol [Internet].2013;16. 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