Metabolite channeling and compartmentation in the human cell line AGE1.HN determined by 13C labeling experiments and 13C metabolic flux analysis

Journal of Bioscience and Bioengineering

Volumn 112, Issue 6, 2011, Pages 616-623

  Niklas, Jens ^a   Sandig, Volker ^b   Heinzle, Elmar ^a  

^a SAARLAND UNIVERSITY   (Germany)

^b PROBIOGEN AG   (Germany)

Author keywords

Biopharmaceutical production; Mammalian cell; Metabolic flux analysis; Pyruvate metabolism; Therapeutic protein

Indexed keywords

BIOPHARMACEUTICALS; CELL LINES; COMPARTMENTATION; CYTOSOLIC; GLUCOSE UPTAKE; GLYCOLYTIC METABOLITES; HUMAN CELL LINES; IMPROVED SUBSTRATE; KETOGLUTARATE; MALIC ENZYMES; MAMMALIAN CELLS; METABOLIC FLUX ANALYSIS; METABOLIC FLUX DISTRIBUTION; METABOLITE CHANNELING; PENTOSE PHOSPHATE PATHWAY; PRODUCTION PROCESS; PYRUVATE METABOLISM; PYRUVATES; RATIONAL DESIGN; SUBSTRATE UPTAKE; TCA CYCLE; THERAPEUTIC PROTEIN;

AMINO ACIDS; BIOMOLECULES; CELL CULTURE; EXPERIMENTS; GLUCOSE; LAKES; MAMMALS; METABOLITES; MITOCHONDRIA; OPTIMIZATION; SUBSTRATES;

METABOLISM;

2 OXOGLUTARIC ACID; ALANINE; ARGININE; ASPARAGINE; ASPARTIC ACID; CYSTEINE; GLUCOSE; GLUTAMIC ACID; GLUTAMINE; GLYCINE; HISTIDINE; ISOLEUCINE; LACTIC ACID; LEUCINE; LYSINE; METHIONINE; OXALOACETIC ACID; PHENYLALANINE; PROLINE; PYRUVIC ACID; SERINE; THREONINE; TRICARBOXYLIC ACID; TRYPTOPHAN; TYROSINE; VALINE;

ARTICLE; CELL COMPARTMENTALIZATION; CELL LABELING; CELL METABOLISM; CITRIC ACID CYCLE; GLUCOSE TRANSPORT; GLYCOLYSIS; HUMAN; HUMAN CELL; METABOLIC RATE; PROCESS OPTIMIZATION; SIGNAL TRANSDUCTION;

CARBON ISOTOPES; CELL LINE; CITRIC ACID CYCLE; GLYCOLYSIS; HUMANS; KINETICS; MODELS, BIOLOGICAL; NEURONS; PENTOSE PHOSPHATE PATHWAY;

MAMMALIA;

EID: 80052644208     PISSN: 13891723     EISSN: 13474421     Source Type: Journal    
DOI: 10.1016/j.jbiosc.2011.07.021     Document Type: Article

References (58)

1. O'Callaghan P.M., James D.C. Systems biotechnology of mammalian cell factories. Brief. Funct. Genomic Proteomic 2008, 7:95-110.
2. Pavlou A.K., Reichert J.M. Recombinant protein therapeutics - success rates, market trends and values to 2010. Nat. Biotechnol. 2004, 22:1513-1519.
3. Walsh G. Biopharmaceutical benchmarks 2006. Nat. Biotechnol. 2006, 24:769-776.
4. Reichert J.M., Rosensweig C.J., Faden L.B., Dewitz M.C. Monoclonal antibody successes in the clinic. Nat. Biotechnol. 2005, 23:1073-1078.
5. Dinnis D.M., James D.C. Engineering mammalian cell factories for improved recombinant monoclonal antibody production: lessons from nature?. Biotechnol. Bioeng. 2005, 91:180-189.
6. Sandig V., Rose T., Winkler K., Brecht R. Mammalian cells. Production of recombinant proteins: novel microbial and eukaryotic expression systems 2005, 233-252. Wiley-VCH, Weinheim, Germany. G. Gellissen (Ed.).
7. Fogolin M.B., Wagner R., Etcheverrigaray M., Kratje R. Impact of temperature reduction and expression of yeast pyruvate carboxylase on hGM-CSF-producing CHO cells. J. Biotechnol. 2004, 109:179-191.
8. Kumar N., Gammell P., Clynes M. Proliferation control strategies to improve productivity and survival during CHO based production culture: a summary of recent methods employed and the effects of proliferation control in product secreting CHO cell lines. Cytotechnology 2007, 53:33-46.
9. Oh H.K., So M.K., Yang J., Yoon H.C., Ahn J.S., Lee J.M., Kim J.T., Yoo J.U., Byun T.H. Effect of N-acetylcystein on butyrate-treated Chinese hamster ovary cells to improve the production of recombinant human interferon-β-1a. Biotechnol. Prog. 2005, 21:1154-1164.
10. Trummer E., Fauland K., Seidinger S., Schriebl K., Lattenmayer C., Kunert R., Vorauer-Uhl K., Weik R., Borth N., Katinger H., Muller D. Process parameter shifting: Part I. Effect of DOT, pH, and temperature on the performance of Epo-Fc expressing CHO cells cultivated in controlled batch bioreactors. Biotechnol. Bioeng. 2006, 94:1033-1044.
11. Rose T., Winkler K., Brundke E., Jordan I., Sandig V. Alternative strategies and new cell lines for high-level production of biopharmaceuticals. Modern biopharmaceuticals 2008, 761-777. Wiley-VCH, Weinheim, Germany. J. Knäblein (Ed.).
12. Blanchard V., Liu X., Eigel S., Kaup M., Rieck S., Janciauskiene S., Sandig V., Marx U., Walden P., Tauber R., Berger M. N-Glycosylation and biological activity of recombinant human alpha1-antitrypsin expressed in a novel human neuronal cell line. Biotechnol. Bioeng. 2011, 108:2118-2128.
13. Kitano H. International alliances for quantitative modeling in systems biology. Mol. Syst. Biol. 2005, 1:2005.0007.
14. Westerhoff H.V., Palsson B.O. The evolution of molecular biology into systems biology. Nat. Biotechnol. 2004, 22:1249-1252.
15. 13C-based flux analysis. Mol. Syst. Biol. 2006, 2:62.
16. Wittmann C. Fluxome analysis using GC-MS. Microb. Cell Fact. 2007, 6:6.
17. Niklas J., Schneider K., Heinzle E. Metabolic flux analysis in eukaryotes. Curr. Opin. Biotechnol. 2010, 21:63-69.
18. Niklas J., Heinzle E. Metabolic flux analysis in systems biology of mammalian cells. Adv. Biochem. Eng. Biotechnol. 2011, (in press). 10.1007/10_2011_99.
19. Kiefer P., Heinzle E., Zelder O., Wittmann C. Comparative metabolic flux analysis of lysine-producing Corynebacterium glutamicum cultured on glucose or fructose. Appl. Environ. Microbiol. 2004, 70:229-239.
20. Kim H.U., Kim T.Y., Lee S.Y. Metabolic flux analysis and metabolic engineering of microorganisms. Mol. Biosyst. 2008, 4:113-120.
21. Wittmann C., Heinzle E. Genealogy profiling through strain improvement by using metabolic network analysis: metabolic flux genealogy of several generations of lysine-producing corynebacteria. Appl. Environ. Microbiol. 2002, 68:5843-5859.
22. Niklas J., Noor F., Heinzle E. Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2. Toxicol. Appl. Pharmacol. 2009, 240:327-336.
23. Wahl A., Sidorenko Y., Dauner M., Genzel Y., Reichl U. Metabolic flux model for an anchorage-dependent MDCK cell line: characteristic growth phases and minimum substrate consumption flux distribution. Biotechnol. Bioeng. 2008, 101:135-152.
24. Deshpande R., Yang T.H., Heinzle E. Towards a metabolic and isotopic steady state in CHO batch cultures for reliable isotope-based metabolic profiling. Biotechnol. J. 2009, 4:247-263.
25. Niklas J., Schrader E., Sandig V., Noll T., Heinzle E. Quantitative characterization of metabolism and metabolic shifts during growth of the new human cell line AGE1.HN using time resolved metabolic flux analysis. Bioprocess Biosyst. Eng. 2011, 34:533-545.
26. 2 in shake-flasks. Biotechnol. Lett. 2003, 25:377-380.
27. 13C] glucose: molecular condensation requires a molecular approach. Am. J. Physiol. 1999, 277:E395-400.
28. Wittmann C. Metabolic flux analysis using mass spectrometry. Adv. Biochem. Eng. Biotechnol. 2002, 74:39-64.
29. Christensen B., Thykaer J., Nielsen J. Metabolic characterization of high- and low-yielding strains of Penicillium chrysogenum. Appl. Microbiol. Biotechnol. 2000, 54:212-217.
30. 13C-lactate nuclear magnetic resonance spectroscopy and metabolite balancing. Biotechnol. Bioeng. 2001, 74:528-538.
31. Grotkjaer T., Akesson M., Christensen B., Gombert A.K., Nielsen J. Impact of transamination reactions and protein turnover on labeling dynamics in (13)C-labeling experiments. Biotechnol. Bioeng. 2004, 86:209-216.
32. Mancuso A., Sharfstein S.T., Tucker S.N., Clark D.S., Blanch H.W. Examination of primary metabolic pathways in a murine hybridoma with carbon-13 nuclear magnetic resonance spectroscopy. Biotechnol. Bioeng. 1994, 44:563-585.
33. Kromer J.O., Fritz M., Heinzle E., Wittmann C. In vivo quantification of intracellular amino acids and intermediates of the methionine pathway in Corynebacterium glutamicum. Anal. Biochem. 2005, 340:171-173.
34. Wittmann C., Hans M., Heinzle E. In vivo analysis of intracellular amino acid labelings by GC/MS. Anal. Biochem. 2002, 307:379-382.
35. Yang T.H., Bolten C.J., Coppi M.V., Sun J., Heinzle E. Numerical bias estimation for mass spectrometric mass isotopomer analysis. Anal. Biochem. 2009, 388:192-203.
36. Antoniewicz M.R., Kelleher J.K., Stephanopoulos G. Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab. Eng. 2007, 9:68-86.
37. 13C metabolic flux analysis using systems parametrized by compactification. BMC Syst. Biol. 2008, 2:29.
38. Berg J.M., Tymoczko J.L., Stryer L. Biochemie 2003, Spektrum Akademischer Verlag, Berlin.
39. Michal G. Biochemical pathways 1999, Spektrum Akademischer Verlag, Heidelberg.
40. Altamirano C., Illanes A., Becerra S., Cairo J.J., Godia F. Considerations on the lactate consumption by CHO cells in the presence of galactose. J. Biotechnol. 2006, 125:547-556.
41. Sidorenko Y., Wahl A., Dauner M., Genzel Y., Reichl U. Comparison of metabolic flux distributions for MDCK cell growth in glutamine- and pyruvate-containing media. Biotechnol. Prog. 2008, 24:311-320.
42. Kim S.H., Lee G.M. Down-regulation of lactate dehydrogenase-A by siRNAs for reduced lactic acid formation of Chinese hamster ovary cells producing thrombopoietin. Appl. Microbiol. Biotechnol. 2007, 74:152-159.
43. 13C isotopomer analysis of glucose and alanine metabolism reveals cytosolic pyruvate compartmentation as part of energy metabolism in astrocytes. Glia 2001, 34:200-212.
44. Bouzier A.K., Goodwin R., de Gannes F.M., Valeins H., Voisin P., Canioni P., Merle M. Compartmentation of lactate and glucose metabolism in C6 glioma cells. A 13c and 1H NMR study. J. Biol. Chem. 1998, 273:27162-27169.
45. 13C flux analysis, Part I: design, construction and validation of a novel multiple reactor system using on-line membrane inlet mass spectrometry. Metab. Eng. 2006, 8:417-431.
46. 13C flux analysis - Part II: in vivo flux estimation of lysine-producing Corynebacterium glutamicum. Metab. Eng. 2006, 8:432-446.
47. 13C2] glucose. Am. J. Physiol. 1998, 274:E843-851.
48. Vo T.D., Lim S.K., Lee W.N.P., Palsson B.O. Isotopomer analysis of cellular metabolism in tissue culture: a comparative study between the pathway and network-based methods. Metabolomics 2006, 2:243-256.
49. Henry O., Jolicoeur M., Kamen A. Unraveling the metabolism of HEK-293 cells using lactate isotopomer analysis. Bioprocess Biosyst. Eng. 2010, 34:263-273.
50. 13C, 1H] COSY NMR spectroscopy. Metab. Eng. 2010, 12:138-149.
51. 13C-labeling experiments: Part II. Flux estimation. Biotechnol. Bioeng. 2008, 100:355-370.
52. Pongratz R.L., Kibbey R.G., Shulman G.I., Cline G.W. Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J. Biol. Chem. 2007, 282:200-207.
53. McKenna M.C. The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J. Neurosci. Res. 2007, 85:3347-3358.
54. Elias C.B., Carpentier E., Durocher Y., Bisson L., Wagner R., Kamen A. Improving glucose and glutamine metabolism of human HEK 293 and Trichoplusia ni insect cells engineered to express a cytosolic pyruvate carboxylase enzyme. Biotechnol. Prog. 2003, 19:90-97.
55. Irani N., Wirth M., van Den Heuvel J., Wagner R. Improvement of the primary metabolism of cell cultures by introducing a new cytoplasmic pyruvate carboxylase reaction. Biotechnol. Bioeng. 1999, 66:238-246.
56. Noguchi Y., Saito A., Miyagi Y., Yamanaka S., Marat D., Doi C., Yoshikawa T., Tsuburaya A., Ito T., Satoh S. Suppression of facilitative glucose transporter 1 mRNA can suppress tumor growth. Cancer Lett. 2000, 154:175-182.
57. Paredes C., Prats E., Cairo J.J., Azorin F., Cornudella L., Godia F. Modification of glucose and glutamine metabolism in hybridoma cells through metabolic engineering. Cytotechnology 1999, 30:85-93.
58. Wlaschin K.F., Hu W.S. Engineering cell metabolism for high-density cell culture via manipulation of sugar transport. J. Biotechnol. 2007, 131:168-176.