Emerging roles for metabolic engineering - Understanding primitive and complex metabolic models and their relevance to healthy and diseased kidney podocytes

Current Chemical Biology

Volumn 2, Issue 1, 2008, Pages 68-82

  Altintas, Mehmet M ^a   Ulgen, Kutlu O ^b   Palmer Toy, Darryl ^c   Shih, Vivian E ^d   Kompala, Dhinakar S ^e   Reiser, Jochen ^a  

^a Department of Medicine   (United States)

^b BOGAZICI UNIVERSITY   (Turkey)

^c KAISER PERMANENTE   (United States)

^d MASSACHUSETTS GENERAL HOSPITAL   (United States)

^e University of Colorado at Boulder   (United States)

Author keywords

Analysis of the health and disease; Intracellular fluxes; Metabolic flux analysis; Podocyte metabolism

Indexed keywords

ACONITATE HYDRATASE; ALPHA3 INTEGRIN; B7 ANTIGEN; CD14 ANTIGEN; CITRATE SYNTHASE; ELECTRON TRANSFERRING FLAVOPROTEIN; ENOLASE; FUMARATE HYDRATASE; GLUTAMATE DEHYDROGENASE; ISOCITRATE DEHYDROGENASE; MALATE DEHYDROGENASE; ORNITHINE OXOACID AMINOTRANSFERASE; PHOSPHOGLUCONATE DEHYDROGENASE; PHOSPHOGLYCERATE MUTASE; PROTEOME; PYRUVATE DEHYDROGENASE; PYRUVATE KINASE; SUCCINATE DEHYDROGENASE; TOLL LIKE RECEPTOR 4; TRANSKETOLASE;

ACCURACY; CELL FUNCTION; CELL METABOLISM; CELL STRUCTURE; DIABETES MELLITUS; FOCAL GLOMERULOSCLEROSIS; GLOMERULUS BASEMENT MEMBRANE; HUMAN; KIDNEY DISEASE; KIDNEY FAILURE; LUPUS ERYTHEMATOSUS NEPHRITIS; MATHEMATICAL MODEL; MEMBRANOUS GLOMERULONEPHRITIS; METABOLIC ENGINEERING; METABOLIC REGULATION; MINIMAL CHANGE GLOMERULONEPHRITIS; MORBIDITY; MORTALITY; NONHUMAN; PATHOGENESIS; PODOCYTE; PREDICTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEINURIA; PROTEOMICS; QUANTITATIVE ANALYSIS; RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS; REVIEW; RISK FACTOR; SENSITIVITY ANALYSIS;

EID: 41749100614     PISSN: 18723136     EISSN: None     Source Type: Journal    
DOI: 10.2174/187231308783334171     Document Type: Review

References (250)

1. Csete ME, Doyle JC. Reverse engineering of biological complexity. Science 2002; 295: 1664-1669.
2. Bailey JE. Towards a science of metabolic engineering. Science 1991; 252: 1668-1674.
3. Stephanopoulos G. Metabolic engineering. Curr Opin Biotech 1994; 5: 196-200.
4. Nielsen J. Metabolic engineering: Techniques for analysis of targets for genetic manipulations. Biotechnol Bioeng 1998; 58: 125-132.
5. Bailey JE. Lessons from metabolic engineering for functional genomics and drug discovery. Nat Biotechnol 1999; 17: 616-618.
6. Koffas M, Roberge C, Lee K, Stephanopoulos G. Metabolic engineering. Annu Rev Biomed Eng 1999; 1: 535-557.
7. Stephanopoulos G. Metabolic fluxes and metabolic engineering. Metab Eng 1999; 1: 1-11.
8. Stephanopoulos G, Stafford DE. Metabolic engineering: A new frontier of chemical reaction engineering. Chem Eng Sci 2002; 57: 2595-2602.
9. Jeong H, Tombor B, Albert R, Oltavi ZN, Barabasi AL. The large-scale organization of metabolic networks. Nature 2000; 407: 651-654.
10. Wagner A, Fell D. The small world inside large metabolic networks. Proc R Soc Lond 2001; 268: 1803-1810.
11. Hatzimanikatis V, Li C, Ionita JA, Broadbelt LJ. Metabolic networks: Enzyme function and metabolite structure. Curr Opin Struct Biol 2004; 14: 300-306.
12. Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res 2004; 32: D277-D280.
13. Krieger CJ, Zhang PF, Mueller LA, et al. MetaCyc: A multiorganism database of metabolic pathways and enzymes. Nucleic Acids Res 2004; 32: D438-D442.
14. 13C labeling experiments. Adv Biochem Eng Biotechnol 1996; 54: 109-154.
15. 13C-NMR, MS and metabolic flux balancing in biotechnology research. Quart Rev Biophys 1998; 31: 41-106.
16. Christensen B, Nielsen J. Isotopomer analysis using GC-MS. Metab Eng 1999; 1: 282-290.
17. Kelleher JK. Flux estimation using isotopic tracers: Common ground for metabolic physiology and metabolic engineering. Metab Eng 2001; 3: 100-110.
18. 13C metabolic flux analysis. Metab Eng 2001; 3: 195-206.
19. 13C-labelling experiments. Eur J Biochem 2602; 269: 2795-2800.
20. Wittmann C. Metabolic flux analysis using mass spectrometry. Adv Biochem Eng Biotechnol 2002; 74: 39-64.
21. Savageau MA, Voit EO, Irvine DH. Biochemical systems theory and metabolic control theory: 1. Fundamental similarities and differences. Math Biosci 1987; 86: 127-145.
22. Savageau MA, Voit EO, Irvine DH. Biochemical systems theory and metabolic control theory: 2. The role of summation and connectivity relationships. Math Biosci 1987; 86: 147-169.
23. Savageau MA. Biochemical systems theory: Operational differences among variant representations and their significance. J Theor Biol 1991; 151: 509-530.
24. Voit EO. Computational analysis of biochemical systems. A practical guide for biochemists and molecular biologists. Cambridge University Press, Cambridge, UK, 2000.
25. Torres NV, Voit EO. Pathway analysis and optimization in metabolic engineering. Cambridge University Press, Cambridge, UK, 2002.
26. Kacser H, Burns JA. The control of flux. Symp Soc Exp Biol 1973; 27: 65-104.
27. Kell DB, Westerhoff HV. Metabolic control theory: Its role in microbiology and biotechnology. FEMS Microbiol. Rev 1986; 39: 305-320.
28. Kacser H, Burns JA, Fell DA. The control of flux. Biochem Soc Trans 1995; 23: 341-366.
29. Fell D. Understanding the control of metabolism. Portland Press, London, UK, 1996,
30. Varma A, Palsson BO. Metabolic flux balancing: Basic concepts, scientific and practical use. Bio-Technol 1994; 12: 994-998.
31. Bonarius HPJ, Schmid G, Tramper J. Flux analysis of underdetermined metabolic networks: The quest for the missing constraints. Trends Biotechnol 1997; 15: 308-314.
32. Lee K, Berthiaume F, Stephanopoulos GN, Yarmush ML. Metabolic flux analysis: A powerful tool for monitoring tissue function. Tissue Eng 1999; 5: 347-368.
33. Christensen B, Nielsen J. Metabolic network analysis: A powerful tool in metabolic engineering. Adv Biochem Eng Biotechnol 2000; 66: 209-231.
34. Cornish-Bowden A, Cardenas ML. From genome to cellular phenotype: A role for metabolic flux analysis? Nat Biotechnol 2000; 18: 267-268.
35. Wiechert W. Modeling and simulation: Tools for metabolic engineering. J Biotechnol 2002; 94: 37-63.
36. Baloo S, Ramkrishna D. Metabolic regulation in bacterial continuous cultures-I. Biotech Bioeng 1991; 20: 1337-1352.
37. Straight J, Ramkrishna D. Complex growth dynamics in batch cultures: Experiments and cybernetic models. Biotech Bioeng 1991; 37: 895-909.
38. Straight J, Ramkrishna D. Cybernetic modeling and regulation of metabolic pathways: Growth on complementary nutrients. Biotechnol Prog 1994; 10: 574-587.
39. Varner J, Ramkrishna D. Application of cybernetic models to metabolic engineering: Investigation of storage pathways. Biotechnol Bioeng 1998; 58: 282-291.
40. Varner J, Ramkrishna D. Metabolic engineering from a cybernetic perspective: I. Theoretical preliminaries. Biotechnol Prog 1999; 15: 407-425.
41. Varner J, Ramkrishna D. Metabolic engineering from a cybernetic perspective: I. Qualitative investigation of nodal architectures and their response to genetic perturbations. Biotechnol Prog 1999; 15: 426-438.
42. Namjoshi A, Ramkrishna D. A cybernetic modeling framework for analysis of metabolic systems. Comp Chem Eng 2005; 29: 487-498.
43. Goodwin BC. Oscillatory organization in cells, a dynamic theory of cellular control processes. Academic Press, New York, 1963.
44. Savageau MA. Biochemical systems analysis. I. Some mathematical properties of the rate laws for the component enzymatic reactions. J Theor Biol 1969; 25: 365-369.
45. Savageau MA. Biochemical systems analysis. II. The steadystate solutions for an n-pool system using a power-law approximation. J Theor Biol 1969; 25: 370-379.
46. Savageau MA. Biochemical systems analysis. III. Dynamic solutions using a power-law approximation. J Theor Biol 1970; 26: 215-226.
47. Hatzimanikatis V, Bailey JE. MCA has more to say. J Theor Biol 1996; 182: 233-242.
48. Stephanopoulos G, Aristidou AA, Nielsen J. Metabolic engineering, principles and methodologies. Academic Press, San Diego, 1998.
49. Edwards JS, Ramakrishna R, Schilling CH, Palsson BO. Metabolic flux balance analysis. In Metabolic Engineering, Lee SY and Papoutsakis ET, editors. Marcel Dekker, New York, 1999; pp. 13-57.
50. Kompala DS. Bacterial growth on multiple substrates. Experimental verification of cybernetic models. Ph. D. thesis. Purdue University, West Lafayette, IN, 1984.
51. Dhurjati P, Ramkrishna D, Flickinger MC, Tsao GT. A cybernetic view of microbial growth: Modeling of cells as optimal strategists. Biotech Bioeng 1985; 27: 1-9.
52. Kompala D, Jansen N, Tsao G, Ramkrishna D. Investigation of bacterial growth on mixed substrates: Experimental evaluation of cybernetic models. Biotech Bioeng 1986; 28: 1044-1055.
53. Holzhütter HG. The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem 2004; 271: 2905-2922.
54. Heijnen J. Approximative kinetic formats used in metabolic network modeling. Biotechnol Bioeng 2005; 91: 534-545.
55. Vaseghi S, Baumeisters, A, Rizzi M, Reuss M. In vivo dynamics of the pentose phosphate pathway in Saccharomyces cerevisiae. Metab Eng 1999; 1: 128-140.
56. Teusink B, Passarge J, Reijenga CA, et al. Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enzymes? Testing biochemistry. Eur J Biochem 2000; 267: 5313-5329.
57. Nielsen J, Jorgensen HS. Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum. Biotechnol Prog 1995; 11: 299-305.
58. Cakir T, Patil KR, Onsan ZI, Ulgen KO, Kirdar B, Nielsen J. Integration of metabolome data with metabolic networks reveals reporter reactions. Mol Syst Biol 2006; 2: doi:10.1038/msb4100085.
59. Tomita M, Hashimoto K, Takahashi K, Shimizu TS, Matsuzaki Y, Miyoshi F, Saito K, Tanida S, Yugi K, Venter JC, Hutchison CA 3rd. E-CELL: Software environment for whole-cell simulation. Bioinformatics 1999; 15: 72-84.
60. Chong L, Ray LB. Whole-istic biology. Science 2002; 295: 1661.
61. Ideker T, Galitski T, Hood LA. New approach to decoding life: Systems biology. Annu Rev Genomics Hum Genet 2001; 2: 343-372.
62. Kitano H. Systems biology: A brief overview. Science 2002; 295: 1662-1664.
63. Oltvai ZN, Barabasi AL. Systems biology. Life's complexity pyramid. Science 2002; 298: 763-764.
64. Henry CM. Systems biology. Chem Eng News 2003; 81: 45-55.
65. Hood L. Systems biology: Integrating technology, biology and computation. Mech Ageing Dev 2003; 124: 9-16.
66. Ideker T. Systems biology 101-What you need to know. Nature Biotechnol 2004; 22: 473-475.
67. Aderem A. Systems biology: Its practice and challenges. Cell 2005; 121: 511-513.
68. Kirschner MW. The meaning of systems biology. Cell 2005; 121: 503-504.
69. Liu ET. Systems biology, integrative biology, predictive biology. Cell 2005; 121: 505-506.
70. Westerhoff HV, Boogerd FC, Bruggeman FJ, Richardson RC, Stephan A, Westerhoff HV. Systems biology in action. Curr Opin Biotechnol 2005; 16: 326-328.
71. Williamson MP. Systems biology: Will it work? Biochem Soc Trans 2005; 33: 503-506.
72. Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev 2003; 83: 253-307.
73. Eddy AA, Schnaper HW. The nephrotic syndrome: From the simple to the complex. Semin Nephrol 1998; 18: 304-316.
74. Kriz W, Lemley KV. The role of the podocyte in glomerulosclerosis. Curr Opin Neph Hyperten 1999; 8: 489-497.
75. Somlo S, Mundel P. Getting a foothold in nephrotic syndrome. Nat Genet 2000; 24: 333-335.
76. Endlich K, Kriz W, Witzgall R. Update in podocyte biology. Curr Opin Nephrol Hypertens 2001; 10: 331-340.
77. Shirato I, Sakai T, Kimura K, Tomino Y, Kriz W. Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis. Am J Pathol 1996; 148: 1283-1296.
78. Smoyer WE, Mundel P. Regulation of podocyte structure during the development of nephrotic syndrome. J Mol Med 1998; 76: 172-183.
79. Reiser J, Von Gersdorff G, Simons M, et al. Novel concepts in understanding and management of glomerular proteinuria. Nephrol Dial Transplant 2002; 17: 951-955.
80. Farquhar MG, Vernier RL, Good RA. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus. J Exp Med 1957; 106: 649-660.
81. Seiler MW, Venkatachalam MA, Cotran RS. Glomerular epithelium: Structural alterations induced by polycations. Science 1975; 189: 390-393.
82. Seiler MR, Rennke HG, Venkatachalam MA, Cotran RS. Pathogenesis of polycation-induced alteration (fusion) of glomerular epithelium. Lab Invest 1977; 36: 48-61.
83. Orlando RA, Takeda T, Zak B, et al. The glomerular epithelial cell anti-adhesin podocalyxin associates with the actin cytoskeleton through interactions with ezrin. J Am Soc Nephrol 2001; 12: 1589-1598.
84. Takeda T, McQuistan T, Orlando RA, Farquhar MG. Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton. J Clin Invest 2001; 108: 289-301.
85. Kawachi H, Kurihara H, Topham PS, et al. Slit diaphragm-reactive nephritogenic MAb 5-1-6 alters expression of ZO-1 in rat podocytes. Am J Physiol Renal Physiol 1997; 273: F984-F993.
86. Fujigaki Y, Nagase M, Hidaka S, et al. Altered anionic GBM components in monoclonal antibody against slit diaphragm-injected proteinuric rats. Kidney Int 1998; 54: 1491-1500.
87. Wharram BL, Goyal M, Gillespie PJ, et al. Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J Clin Invest 2000; 106: 1281-1290.
88. Smoyer WE, Mundel P, Gupta A, Welsh MJ. Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol 1997; 273: F150-157.
89. Kaplan J, Pollak MR. Familial focal segmental glomerulosclerosis. Curr Opin Nephrol Hypertens 2001; 10: 183-187.
90. Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP. The renal glomerulus of mice lacking s-laminin/laminin beta-2: Nephrosis despite molecular compensation by laminin beta-1. Nat Genet 1995; 10: 400-406.
91. Kreidberg JA, Donovan MJ, Goldstein SL, et al. Alpha-3 beta-1 integrin has a crucial role in kidney and lung organogenesis. Development 1996; 122: 3537-3547.
92. Miner JH, Sanes JR. Molecular and functional defects in kidneys of mice lacking collagen alpha-3(IV): Implications for Alport syndrome. J Cell Biol 1996; 135: 1403-1413.
93. Miner JH, Li C. Defective glomerulogenesis in the absence of laminin alpha-5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol 2000; 217: 278-289.
94. Raats CJ, Van Den Born J, Berden JH. Glomerular heparan sulfate alterations: Mechanisms and relevance for proteinuria. Kidney Int 2000, 57: 385-400.
95. Regele HM, Fillipovic E, Langer B, et al. Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis. J Am Soc Nephrol 2000; 11: 403-412.
96. Kretzler M, Teixeira VP, Unschuld PG, et al. Integrin-linked kinase as a candidate downstream effector in proteinuria. FASEB J 2001; 15: 1843-1845.
97. Morello R, Zhou G, Dreyer SD, et al. Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nat Genet 2001; 27: 205-208.
98. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, et al. Positionally cloned gene for a novel glomerular protein -nephrin- is mutated in congenital nephrotic syndrome. Mol Cell 1998; 1: 575-582.
99. Lenkkeri U, Mannikko M, McCready P, et al. Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 1999; 64: 51-61.
100. Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest 2003; 112: 209-221.
101. Reiser J, Mundel P. Danger signaling by glomerular podocytes defines a novel function of inducible B7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol 2004; 15: 2246-2248.
102. Reiser J, Oh J, Shirato I, et al. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha-3 integrin. J Biol Chem 2004; 279: 34827-34832.
103. Reiser J, Von Gersdorff G, Loos M, et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004; 113: 1390-1397.
104. Reiser J, Pixley FJ, Hug A, et al. Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases. Kidney Int 2000; 57: 2035-2042.
105. 13C metabolic flux analysis. Metab Eng 2001; 3: 265-283.
106. Klapa MI, Park SM, Sinskey AJ, Stephanopoulos G. Metabolite and isotopomer balancing in the analysis of metabolic cycles: I. Theory. Biotechnol Bioeng 1999; 62: 375-391.
107. Bonarius HPJ, Hatzimanikatis V, Meesters KPH, de Gooijer CD, Schmid G, Tramper J. Metabolic flux analysis of hybridoma cells in different culture media using mass balances. Biotechnol Bioeng 1996; 50: 299-318.
108. Xie L, Wang DC. Material balance studies on animal cell metabolism using a stoichiometrically based reaction network. Biotechnol Bioeng 1996; 52: 579-590.
109. Follstad BD, Balcarcel R, Wang DIC, Stephanopoulos G. Metabolic flux analysis of hybridoma continuous culture steady-state multiplicity. Biotechnol Bioeng 1999; 63: 675-683.
110. Balcarcel RR, Clark LM. Metabolic screening of mammalian cell cultures using well-plates. Biotechnol Prog 2003; 19: 98-108.
111. Nyberg GB, Balcarcel RP, Follstad BD, Stephanopoulos G, Wang DIC. Metabolism of peptide amino acids by chinese hamster ovary cells grown in a complex medium. Biotechnol Bioeng 1999; 62: 324-335.
112. Nadeau I, Sabatie J, Koehl M, Perrier M, Kamen A. Human 293 cell metabolism in low glutamine-supplied culture: Interpretation of metabolic changes through metabolic flux analysis. Metab Eng 2000; 2: 277-292.
113. Nadeau I, Jacob D, Perrier M, Kamen A. 293SF metabolic flux analysis during cell growth and infection with an adenoviral vector. Biotechnol Prog 2000; 16: 872-884.
114. Chan C, Berthiaume F, Lee K, Yarmush ML. Metabolic flux analysis of cultured hepatocytes exposed to plasma. Biotechnol Bioeng 2003; 81: 33-49.
115. Arai K, Lee K, Berthiaume F, Tompkins RG, Yarmush ML. Intrahepatic amino acid and glucose metabolism in a D-galactosamine-induced rat liver failure model. Hepatology 2001; 34: 360-371.
116. Kahn P. From genome to proteome: Looking at a cell's proteins. Science 1995; 270: 369-370.
117. Wilkins MR, Sanchez JC, Gooley AA, et al. Progress with proteome projects: Why all proteins expressed by a genome should be identified and how to do it. Biotechnol Genet Eng Rev 1996; 13: 19-50.
118. Liebler DC. Introduction to proteomics: Tools for the new biology. Humana Press, Totowa, NJ, 2001.
119. Palmer-Toy DE, Kuzdzal S, Chan DW. Proteomic approaches to tumor marker discovery. In 'Tumor markers: Physiology, pathobiology, Technology and clinical applications', Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz M (eds.), AACC Press, Washington DC, 2002; pp. 391-400.
120. Yan JX, Devenish AT, Wait R, Stone T, Lewis S, Fowler S. Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics 2002; 2: 1682-1698.
121. Lilley KS, Dupree P. Methods of quantitative proteomics and their application to plant organelle characterization. J Exp Bot 2006; 57: 1493-1499.
122. Wolters DA, Washburn MP, Yates JR 3rd. An automated multidimensional protein identification technology for shotgun proteomics. Anal Chem 2001; 73: 5683-5690.
123. Ransom, RF. Podocyte proteomics. Contrib Nephrol 2004; 141: 189-211.
124. Ransom RF, Vega-Warner V, Smoyer WE, Klein J. Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes. Kidney Int 2005; 67: 1275-1285.
125. Dreger M. Proteome analysis at the level of subcellular structures. Eur J Biochem 2003; 270: 589-599.
126. Chen P, Harcum SW. Effects of amino acid additions on ammonium stressed CHO cells. J Biotechnol 2005; 117: 277-286.
127. Linz M, Zeng AP, Wagner R, Deckwer WD. Stoichiometry, kinetics and regulation of glucose and amino acid metabolism of a recombinant BHK cell line in batch and continuous cultures. Biotechnol Prog 1997; 13: 453-463.
128. Schneider M, Marison IW, von Stockar U. The importance of ammonia in mammalian cell culture. J Biotechnol 1996; 46: 161-185.
129. Zeilke HR, Ozand PT, Tildon JT, Sevdalian DA, Cornblath M. Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts. J Cell Physiol 1978; 95: 41-48.
130. Glacken MW, Huang C, Sinskey AJ. Mathematical descriptions of hybridoma culture kinetics: III. Simulation of fed-batch bioreactors. J Biotechnol 1989; 10: 39-66.
131. Fitzpatrick L, Jenkins HA, Butler M. Glucose and glutamine metabolism of a murine B-lymphocyte hybridoma grown in batch culture. Appl Biochem Biotechnol 1993; 43: 93-116.
132. Elias CB, 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.
133. Neermann J, Wagner R. Comparative analysis of glucose and glutamine metabolism in transformed mammalian cell lines, insect and primary liver cells. J Cell Phys 1996; 166: 152-169.
134. Calik P, Calik G, Takac S, Ozdamar TH. Metabolic flux analysis for serine alkaline protease fermentation by Bacillus licheniformis in a defined medium: Effects of the oxygen transfer rate. Biotechnol Bioeng 1999; 64: 151-167.
135. Dauner M, Storni T, Sauer U. Bacillus subtilis metabolism and energetics in carbon-limited and excess-carbon chemostat culture. J Bacteriol 2001; 183: 7308-7317.
136. Goel A, Ferrance J, Jeong J, Ataa MM. Analysis of metabolic fluxes in batch and continuous cultures of Bacillus subtilis. Biotechnol Bioeng 1993; 42: 686-696.
137. Sauer U, Hatzimanikatis V, Hohmann HP, Manneberg M, van Loon AP, Bailey JE. Physiology and metabolic fluxes of wild-type and riboflavin-producing Bacillus subtilis. Appl Environ Microbiol 1996; 62: 3687-3696.
138. Sauer U, Hatzimanikatis V, Bailey JE, Hochuli M, Szyperski T, Wuthrich K. Metabolic fluxes in riboflavin-producing Bacillus subtillis. Nat Biotechnol 1997; 15: 448-452.
139. Dauner M, Bailey JE, Sauer U. Metabolic flux analysis with a comprehensive isotopomer model in Bacillus subtilis. Biotechnol Bioeng 2001; 76: 144-156.
140. Zhu Y, Chen X, Chen T, Zhao X. Enhancement of riboflavin production by overexpression of acetolactate synthase in a pta mutant of Bacillus subtilis. FEMS Microbiol Lett 2007; 266: 224-230.
141. Reardon KF, Scheper TH, Bailey JE. Metabolic pathway rates and culture fluorescence in batch fermentations of Clostridium acetobutylicum. Biotechnol Prog 1987; 3: 153-167.
142. Desai RP, Harris LM, Welker NE, Papoutsakis ET. Metabolic flux analysis elucidates the importance of acid-formation pathways in regulating solvent production by Clostridium acetobutylicum. Metab Eng 1999; 1: 206-213.
143. Desai RP, Nielsen LK, Papoutsakis ET. Stoichiometric modeling of Clostridium acetobutylicum fermentations with non-linear constraints. J Biotechnol 1999; 71: 191-205.
144. Harris LM, Blank L, Desai RP, Welker NE, Papoutsakis ET. Fermentation characterization and flux analysis of recombinant strains of Clostridium acetobutylicum with an inactivated solR gene, J Ind Microbiol Biotechnol 2001; 27: 322-328.
145. Desvaux M, Petitdemange H. Flux analysis of the metabolism of Clostridium cellulolyticum grown in cellulose-fed continuous culture on a chemically defined medium under ammonium-limited conditions. Appl Environ Microbiol 2001; 67: 3846-3851.
146. Desvaux M, Guedon E, Petitdemange H. Metabolic flux in cellulose batch and cellulose-fed continuous cultures of Clostridium cellulolyticum in response to acidic environment. Microbiology 2001; 147: 1461-1471.
147. Zupke C, Stephanopoulos G. Modeling of isotope distributions and intracellular fluxes in metabolic networks using atom mapping matrices. Biotechnol Prog 1994; 10: 489-498.
148. Kimura E. Metabolic engineering of glutamate production. Adv Biochem Eng Biotechnol 2003; 79: 37-57.
149. Shirai T, Matsuzaki K, Kuzumoto M, et al. Precise metabolic flux analysis of Coryneform bacteria by gas chromatography-mass spectrometry and verification by nuclear magnetic resonance. J Biosci Bioeng 2006; 101: 413-424.
150. Vallino JJ, Stephanopoulos G. Metabolic flux distributions, in Corynebacterium glutamicum during growth and lysine overproduction. Biotechnol Bioeng 1993; 41: 633-646.
151. Vallino JJ, Stephanopoulos G. Carbon flux distributions at the glucose-6-phosphate branch point in Corynebacterium glutamicum during lysine overproduction. Biotechnol Prog 1994; 10: 327-334.
152. Vallino JJ, Stephanopoulos G. Carbon flux distributions at the pyruvate branch point in C. glutamicum during lysine overproduction. Biotechnol Prog 1994; 10: 327-334.
153. Vallino JJ, Stephanopoulos G. Metabolic flux distributions in Corynebacterium glutamicum during growth and lysine overproduction. Biotechnol Bioeng 2000; 67: 872-885.
154. Marx A, de Graaf AA, Wiechert W, Eggeling L, Sahm H. Determination of the fluxes in the central metabolism of Corynebacterium glutamicum. Biotechnol Bioeng 1996; 49: 111-129.
155. Wittmann C, Heinzle E. Modeling and experimental design for metabolic flux analysis of lysine-producing Corynebacteria by mass spectrometry. Metab Eng 2001; 3: 173-191.
156. 13C-labeling-based metabolic flux analysis and L-lysine production. Metab Eng 2003; 5: 96-107.
157. Yang J, Wongsa S, Kadirkamanathan V, Billings SA, Wright PC. Metabolic flux estimation - A self-adaptive evolutionary algorithm with singular value decomposition. IEEE/ACM Trans Comp Biol Bioinformatics 2007; 4: 126-138.
158. 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.
159. Wittmann C, Kiefer P, Zelder O. Metabolic fluxes in Corynebacterium glutamicum during lysine production with sucrose as carbon source. Appl. Environ Microbiol 2004; 70: 7277-7287.
160. Park SM, Sinskey AJ, Stephanopoulos G. Metabolic and physiological studies of Corynebacterium glutamicum mutants. Biotechnol Bioeng 1997; 55: 864-879.
161. 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: 265-274.
162. Pons A, Dussap CG, Pequignot C, Gros JB. Metabolic flux distribution in Cornybacterium melassecola ATCC 17965 for various carbon sources. Biotechnol Bioeng 1996, 51: 177-189.
163. Majewski RA, Domach MM. Simple constrained optimization view of acetate overflow in Escherichia coli. Biotechnol Bioeng 1990; 35: 732-738.
164. Delgado J, Liao JC. Inverse flux analysis for reduction of acetate excretion in Escherichia coli. Biotechnol Prog 1997; 13: 361-367.
165. Varma A, Palsson BO. Metabolic capabilities of Escherichia coli. II. Optimal growth patterns. J Theor Biol 1993; 165: 503-522.
166. Aristidou AA, San KY, Bennett GN. Metabolic flux analysis of Escherichia coli expressing the Bacillus subtilis acetolactate synthase in batch and continuous cultures. Biotechnol Bioeng 1999; 63: 737-749.
167. Yang YT, Aristidou AA, San KY, Bennett GN. Metabolic flux analysis of Escherichia coli deficient in the acetate production pathway and expressing the Bacillus subtilis acetolactate synthase. Metab Eng 1999; 1: 26-34.
168. Edwards JS, Palsson BO. Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions. BMC Bioinformatics 2000; 1: 1-10.
169. Burgard AP, Maranas CD. Probing the performance limits of the Escherichia coli metabolic network subject to gene additions or deletions. Biotechnol Bioeng 2001; 74: 364-375.
170. Emmerling M, Dauner M, Ponti A, et al. Metabolic flux responses to pyruvate kinase knockout in Escherichia coli. J Bacteriol 2002; 184: 152-164.
171. Hua Q, Yang C, Baba T, Mori H, Shimizu K. Responses of the central metabolism in Escherichia coli to phosphoglucose isomerase and glucose-6-phosphate dehydrogenase knockouts. J Bacteriol 2003; 185: 7053-7067.
172. Yang C, Hua Q, Baba T, Mori H, Shimizu K. Analysis of Escherichia coli anaplerotic metabolism and its regulation mechanisms from the metabolic responses to altered dilution rates and phosphoenolpyruvate carboxykinase knockout. Biotechnol Bioeng 2003; 84: 129-144.
173. 13C-labeling experiments together with measurements of enzyme activities and intracellular metabolite concentrations. Appl Microbiol Biotechnol 2004; 63: 407-417.
174. 13C-labelling experiments together with enzyme activity assays and intracellular metabolite measurements. FEMS Microbiol Lett 2004; 235: 17-23.
175. Zhao J, Baba T, Mori H, Shimizu K. Effect of zwf gene knockout on the metabolism of Escherichia coli grown on glucose or acetate. Metab Eng 2004; 6: 164-174.
176. Diaz-Ricci JC, Tsu M, Bailey JE. Influence of expression of the pet operon on intracellular metabolic fluxes of Escherichia coli. Biotechnol Bioeng 1992; 39: 59-65.
177. Varma A, Boesch BW, Palsson BO. Stoichiometric interpretation of Escherichia coli glucose catabolism under various oxygenation rates. Appl Environ Microb 1993; 59: 2465-2473.
178. Varma A, Palsson BO. Stoichiometric flux balance models quantitatively predict growth and metabolic byproduct secretion in wild type Escherichia coli W3110. Appl Environ Microbiol 1994; 60: 3724-3731.
179. Varma A, Palsson BO. Parametric sensitivity of stoichiometric flux balance models applied to wild type Escherichia coli metabolism. Biotechnol Bioeng 1995; 45: 69-79.
180. Holms WH. Flux analysis and control of the central metabolic pathways in Escherichia coli. FEMS Microbiol Rev 1996; 19: 85-116.
181. Schilling CH, Edwards JS, Letscher D, Palsson BO. Combining pathway analysis with flux balance analysis for the comprehensive study of metabolic systems. Biotechnol Bioeng 2000; 71: 286-306.
182. Keasling JD, Van Dien SJ, Pramanik J. Engineering polyphosphate metabolism in Escherichia coli: Implications for bioremediation of inorganic contaminants. Biotechnol Bioeng 1998; 58: 231-239.
183. Hong SH, Lee SY. Metabolic flux analysis for succinic acid production by recombinant Escherichia coli with amplified malic enzyme activity. Biotechnol Bioeng 2001; 74: 89-95.
184. Lee SY, Hong SH, Moon SY. In silico metabolic pathway analysis and design: Succinic acid production by metabolically engineered Escherichia coli as an example. Genome Inform 2002; 13: 214-223.
185. Sanchez AM, Bennett GN, San KY. Batch culture characterization and metabolic flux analysis of succinate-producing Escherichia coli strains. Metab Eng 2006; 8: 209-226.
186. Bai DM, Zhao XM, Li XG, Xu SM. Strain improvement and metabolic flux analysis in the wild-type and a mutant Lactobacillus lactis strain for L(+)-lactic acid production. Biotechnol Bioeng 2004; 88: 681-689.
187. Naeimpoor F, Mavituna F. Metabolic flux analysis in Streptomyces coelicolor under various nutrient limitations. Metab Eng 2000; 2: 140-148.
188. Kim HB, Smith CP, Micklefield J, Mavituna F. Metabolic flux analysis for calcium dependent antibiotic (CDA) production in Streptomyces coelicolor. Metab Eng 2004; 6: 313-325.
189. Daae EB, Ison AP. Classification and sensitivity analysis of a proposed primary metabolic reaction network for Streptomyces lividans. Metab Eng 1999; 1: 153-165.
190. Avignone Rossa C, White J, Kuiper A, Postma PW, Bibb M, Teixeira de Mattos MJ. Carbon flux distribution in antibiotic-producing chemostat cultures of Streptomyces lividans. Metab Eng 2002; 4: 138-150.
191. 31P-NMR spectroscopy. Arch Microbiol 1999; 171: 371-385.
192. Kumar S, Punekar NS, SatyaNarayan V, Venkatesh KV. Metabolic fate of glutamate and evaluation of flux through the 4-aminobutyrate (GABA) shunt in Aspergillus niger. Biotechnol Bioeng 2000; 67: 575-584.
193. 13C tracer experiments and metabolite balancing for metabolic flux analysis: Comparing two approaches. Biotechnol Bioeng 1998; 58: 254-257.
194. Granstrom TB, Aristidou AA, Jokela J, Leisola M. Growth characteristics and metabolic flux analysis of Candida milleri. Biotechnol Bioeng 2000; 70: 197-207.
195. Cao Z, Gao H, Liu M, Jiao P. Engineering the acetyl-CoA transportation system of Candida tropicalis enhances the production of dicarboxylic acid. Biotechnol J 2006; 1: 68-74.
196. Granstrom T, Aristidou AA, Leisola M. Metabolic flux analysis of Candida tropicalis growing on xylose in an oxygen-limited chemostat. Metab Eng 2002; 4: 248-256.
197. Jorgensen H, Nielsen J, Villadsen J, Mollgaard H. Metabolic flux distributions in Penicillium chrysogenum during fed-batch cultivations. Biotechnol Bioeng 1995; 46: 117-131.
198. Henriksen CM, Christensen LH, Nielsen J, Villadsen J. Growth energetics and metabolic fluxes in continuous cultures of Penicillium chrysogenum. J Biotechnol 1996; 45: 149-164.
199. 13C-labeled glucose. Biotechnol Bioeng 2000; 68: 652-659.
200. 1H] COSY NMR measurements and cumulative bondomer simulation. Biotechnol Bioeng 2003; 83: 75-92.
201. Van Gulik WM, Heijnen JJ. A metabolic network stoichiometry analysis of microbial growth and product formation. Biotechnol Bioeng 1995; 48: 681-698.
202. Nissen TL, Schulze U, Nielsen J, Villadsen J. Flux distributions in anaerobic, glucose-limited continuous cultures of Saccharomyces cerevisiae. Microbiology 1997; 143: 203-218.
203. Franzen CJ. Metabolic flux analysis of RQ-controlled microaerobic ethanol production by Saccharomyces cerevisiae. Yeast 2003; 20: 117-132.
204. Hjersted JL, Henson MA. Optimization of fed-batch Saccharomyces cerevisiae fermentation using dynamic flux balance models. Biotechnol Prog 2006; 22: 1239-1248.
205. Hjersted JL, Henson MA, Mahadevan R. Genome-scale analysis of Saccharomyces cerevisiae metabolism and ethanol production in fed-batch culture. Biotechnol Bioeng 2007; 97: 1190-1204.
206. Tai SL, Daran-Lapujade P, Luttik MAH, et al. Control of the glycolytic flux in Saccharomyces cerevisiae grown at low temperature: A multi-level analysis in anaerobic chemostat cultures. J Biol Chem 2007; 282: 10243-10251.
207. Cortassa S, Aon JC, Aon MA. Fluxes of carbon, phosphorylation, and redox intermediates during growth of Saccharomyces cerevisiae on different carbon sources. Biotechnol Bioeng 1995; 47: 193-208.
208. Lee TH, Kim MY, Ryu YW, Seo JH. Estimation of theoretical yield for ethanol production from D-xylose by recombinant Saccharomyces cerevisiae using metabolic pathway synthesis algorithm. J Microbiol Biotechnol 2001; 11: 384-388.
209. Wahlbom CF, Eliasson A, Hahn-Hagerdal B. Intracellular fluxes in a recombinant xylose-utilizing Saccharomyces cerevisiae cultivated anaerobically at different dilution rates and feed concentrations. Biotechnol Bioeng 2001; 72: 289-296.
210. Wahlbom CF, Hahn-Hagerdal B. Furfural, 5-hydroxymethyl furfural, and acetoin act as external electron acceptors during anaerobic fermentation of xylose in recombinant Saccharomyces cerevisiae. Biotechnol Bioeng 2002; 78: 172-178.
211. Pitkanen JP, Aristidou A, Salusjarvi L, Ruohonen L, Penttila M. Metabolic flux analysis of xylose metabolism in recombinant Saccharomyces cerevisiae using continuous culture. Metab Eng 2003; 5: 16-31.
212. Sonderegger M, Jeppsson M, Hahn-Hagerdal B, Sauer U. Molecular basis for anaerobic growth of Saccharomyces cerevisiae on xylose, investigated by global gene expression and metabolic flux analysis. Appl Environ Microbiol 2004; 70: 2307-2317.
213. Grotkjaer T, Christakopoulos P, Nielsen J, Olsson L. Comparative metabolic network analysis of two xylose fermenting recombinant Saccharomyces cerevisiae strains. Metab Eng 2005; 7: 437-444.
214. Aon JC, Cortassa S. Involvement of nitrogen metabolism in the triggering of ethanol fermentation in aerobic chemostat cultures of Saccharomyces cerevisiae. Metab Eng 2001; 3: 250-264.
215. Cakir T, Arga KY, Altintas MM, Ulgen K. Flux analysis of the recombinant Saccharomyces cerevisiae YPB-G utilizing starch for optimum ethanol production. Process Biochem 2004; 39: 2097-2108.
216. 13C-labelling data. FEMS Yeast Res 2007; 7: 216-231.
217. Jin S, Ye K, Shimizu K. Metabolic flux distributions in recombinant Saccharomyces cerevisiae during foreign protein production. J Biotechnol 1997; 54: 161-174.
218. Moller K, Christensen B, Forster J, Pikur J, Nielsen J, Olsson L. Aerobic glucose metabolism of Saccharomyces kluyveri: Growth, metabolite production and quantification of metabolic fluxes. Biotechnol Bioeng 2002; 77: 186-193.
219. Cruz HJ, Moreira JL, Carrondo MJT. Metabolic shifts by nutrient manipulation in continuous cultures of BHK cells. Biotechnol Bioeng 1999; 66: 104-113.
220. Nyberg GB, Balcarcel RR, Follstad BD, Stephanopoulos G, Wang DI. Metabolic effects on recombinant interferon-gamma glycosylation in continuous culture of Chinese hamster ovary cells. Biotechnol Bioeng 1999; 62: 336-347.
221. Altamirano C, Illanes A, Casablancas A, Gamez X, Cairo JJ, Godia C. Analysis of CHO cells metabolic redistribution in a glutamate-based defined medium in continuous culture. Biotechnol Prog 2001; 17: 1032-1041.
222. Altamirano C, Illanes A, Becerra S, Cairo JJ, Godia F. Considerations on the lactate consumption by CHO cells in the presence of galactose. J Biotechnol 2006; 125: 547-556.
223. Henry O, Perrier M, Kamen A. Metabolic flux analysis of HEK-293 cells in perfusion cultures for the production of adenoviral vectors. Metab Eng 2005; 7: 467-476.
224. Xie L, Wang D. Energy metabolism and ATP balance in animal cell cultivation using a stoichiometrically based reaction network. Biotechnol Bioeng 1996; 52: 591-601.
225. Zupke C, Sinskey AJ, Stephanopoulos G. Intracellular flux analysis applied to the effect of dissolved oxygen on hybridomas. Appl Microbiol Biotechnol 1995; 44: 27-36.
226. Savinell JM, Palsson BO. Network analysis of intermediary metabolism using linear optimization: II. Interpretation of hybridoma cell metabolism. J Theor Biol 1992; 154: 455-473.
227. 13C NMR. Biotechnol Bioeng 1995; 45: 292-303.
228. 13C-lactate nuclear magnetic resonance spectroscopy and metabolite balancing. Biotechnol Bioeng 2001; 74: 528-538.
229. Xie L, Wang D. Applications if improved stoichiometric model in medium design and fed-batch cultivation of animal cells in bioreactor. Cytotechnology 1994; 15: 17-29.
230. Xie L, Wang D. Stoichiometric analysis of animal cell growth and its application in medium design. Biotechnol Bioeng 1994; 43: 1164-1174.
231. Xie L, Wang D, High cell density and high monoclonal antibody production through medium design and rational control in a bioreactor. Biotechnol Bioeng 1996; 51: 725-729.
232. Xie L, Wang D. Integrated approaches to the design of media and feeding strategies for fed-batch cultures of animal cells. Trends Biotechnol 1997; 15: 109-113.
233. De Alwis DM, Dutton RL, Scharer J, Moo-Young M. Statistical methods in media optimization for batch and fed-batch animal cell culture. Bioprocess Biosyst Eng 2007; 30: 107-113.
234. Gambhir A, Korke R, Lee J, Fu PC, Europa A, Hu WS. Analysis of cellular metabolism of hybridoma cells at distinct physiological states. J Biosci Bioeng 2003; 95: 317-327.
235. Si Y. Ybon J, Lee K. Flux profile and modularity analysis of time-dependent metabolic changes of de novo adipocyte formation. Am J Physiol Endocrinol Metab 2007; 292: E1637-E1646.
236. Fell DA, Small JR. Fat synthesis in adipose tissue. An examination of stoichiometric constraints. Biochem J 1986; 238: 781-786.
237. Chatziioannou A, Palaiologos G, Kolisisa FN. Metabolic flux analysis as a tool for the elucidation of the metabolism of neuro-transmitter glutamate. Metab Eng 2003; 5: 201-210.
238. Alsan S, Cakir T, Saybasili H, Akin A, Ulgen K. Modelling of neuron-astrocyte coupling via stoichiometric modelling technique. Poster presented at ESBES5, Stuttgart-Germany, 8-11 September 2004.
239. Vo TD, Greenberg HJ, Palsson BO. Reconstruction and functional characterization of the human mitochondrial metabolic network based on proteomic and biochemical data. J Biol Chem 2004; 279: 39532-39540.
240. Thiele I, Price ND, Vo TD, Palsson BO. Candidate metabolic network states in human mitochondria: Impact of diabetes, ischemia and diet. J Biol Chem 2005; 280: 11683-11695.
241. 2- Metab Eng 2003; 5: 221-229.
242. Lee K, Berthiaume F, Stephanopoulos GN, Yarmush ML, Profiling of dynamic changes in hypermetabolic livers. Biotechnol Bioeng 2003; 83: 400-415.
243. Nolan RP, Fenley AP, Lee K. Identification of distributed metabolic objectives in the hypermetabolic liver by flux and energy balance analysis. Metab Eng 2006; 8: 30-45.
244. Calik P, Akbay A. Mass flux balance-based model and metabolic flux analysis for collagen synthesis in the fibrogenesis process of human liver. Med Hypoth 2000; 55: 5-14.
245. Chan C, Berthiaume F, Lee K, Yarmush ML. Metabolic flux analysis of hepatocyte function in hormone and amino acid supplemented plasma. Metab Eng 2003; 5: 1-15.
246. Yokoyama T, Banta S, Berthiaume F, Nagrath D, Tompkins RG, Yarmush ML. Evolution of intrahepatic carbon, nitrogen and energy metabolism in a D-galactosamine-induced rat liver failure model. Metab Eng 2005; 7: 88-103.
247. Yamaguchi Y, Yu YM, Zupke C, et al. Effect of burn injury on glucose and nitrogen metabolism in the liver: Preliminary studies in a perfused liver system. Surgery 1997; 121: 95-303.
248. Lee K, Berthiaume F, Stephanopoulos GN, Yarmush DM, Yarmush ML. Metabolic flux analysis of postburn hepatic hypermetabolism. Metab Eng 2000; 2: 312-327.
249. Banta S, Yokoyama T, Berthiaume F, Yarmush ML. Effects of dehydroepiandrosterone administration on rat hepatic metabolism following thermal injury. J Surg Res 2005; 127:93-105.
250. Banta S, Yokoyama T, Berthiaume F, Yarmush ML. Quantitative effects of thermal injury and insulin on the metabolism of the skeletal muscle using the perfused rat hindquarter preparation. Biotechnol Bioeng 2004; 88: 613-629.