Literature Cited

  • 1
    Stephanopoulos G. Metabolic fluxes and metabolic engineering. Metab Eng. 1999; 1: 111.
  • 2
    Wiechert W. 13C metabolic flux analysis. Metab Eng. 2001; 3: 195206.
  • 3
    Wiechert W, de Graaf AA. In vivo stationary flux analysis by 13C labeling experiments. Adv Biochem Eng Biotechnol. 1996; 54: 109154.
  • 4
    Zamboni N, Fendt S, Rühl M, Sauer U. (13)C-based metabolic flux analysis. Nat Protoc. 2009; 4: 878892.
  • 5
    Henry CS, Broadbelt LJ, Hatzimanikatis V. Thermodynamics-based metabolic flux analysis. Biophys J. 2007; 92: 17921805.
  • 6
    Stephanopoulos GN, Vallino JJ. Network rigidity and metabolic engineering in metabolite overproduction. Science. 1991; 9646: 16751681.
  • 7
    Nöh K, Grönke K, Luo B, Takors R, Oldiges M, Wiechert W. Metabolic flux analysis at ultra short time scale: isotopically non-stationary 13C labeling experiments. J Biotechnol. 2007; 129: 249267.
  • 8
    Tang YJ, Martin HG, Myers S, Rodriguez S, Baidoo EEK, Keasling JD. Advances in analysis of microbial metabolic fluxes via 13C isotopic labeling. Mass Spectrom Rev. 2009; 28: 362375.
  • 9
    Fischer E, Sauer U. Metabolic flux profiling of Escherichia coli mutants in central carbon metabolism using GC-MS. Eur J Biochem. 2003; 270: 880891.
  • 10
    Alper H, Jin Y-S, Moxley JF, Stephanopoulos G. Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng. 2005; 7: 155164.
  • 11
    Bro C, Regenberg B, Förster J, Nielsen J. In silico aided metabolic engineering of Saccharomyces cerevisiae for improved bioethanol production. Metab Eng. 2006; 8: 102111.
  • 12
    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 USA. 2007; 104: 77977802.
  • 13
    Lee SJ, Lee D, Kim TY,Kim BH, Lee J, Lee SY. Metabolic engineering of Escherichia coli for enhanced production of succinic acid, based on genome comparison and in silico gene knockout simulation. Appl Environ Microbiol. 2005; 71: 78807887.
  • 14
    Wiechert W, Möllney M, Petersen S, de Graaf AA. A universal framework for 13C metabolic flux analysis. Metab Eng. 2001; 3: 265283.
  • 15
    Rao CV, Arkin AP. Control motifs for intracellular regulatory networks. Annu Rev Biomed Eng. 2001; 3: 391419.
  • 16
    Thomas R, Thieffry D. Dynamical behaviour of biological regulatory networks. I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. Bull Math Biol. 1995; 57: 247276.
  • 17
    Covert MW, Schilling CH, Palsson B. Regulation of gene expression in flux balance models of metabolism. J Theor Biol. 2001; 213: 7388.
  • 18
    Fendt S, Buescher JM, Rudroff F, Picotti P, Zamboni N, Sauer U. Tradeoff between enzyme and metabolite efficiency maintains metabolic homeostasis upon perturbations in enzyme capacity. Mol Syst Biol. 2010; 6: 356: 1–11.
  • 19
    Fell DA. Metabolic control analysis: a survey of its theoretical and experimental development. Biochem J. 1992; 330: 313330.
  • 20
    Brown GC, Hafner RP, Brand MD. A “top-down” approach to the determination of control coefficients in metabolic control theory. Eur J Biochem. 1990; 188: 321325.
  • 21
    Stephanopoulos GN, Simpson TW. Flux amplification in complex metabolic networks. Chem Eng Sci. 1997; 52: 26072627.
  • 22
    Westerhoff HV, Chen YD. How do enzyme activities control metabolite concentrations? An additional theorem in the theory of metabolic control. Eur J Biochem. 1984; 142: 425430.
  • 23
    Haverkorn van Rijsewijk BRB, Nanchen A, Nallet S, Kleijn RJ, Sauer U. Large-scale 13C-flux analysis reveals distinct transcriptional control of respiratory and fermentative metabolism in Escherichia coli. Mol Syst Biol. 2011; 7: 477: 1–12.
  • 24
    Weinberg RA. The Biology of Cancer. New York, NY: Garland Science; 2007.
  • 25
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 5770.
  • 26
    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011; 11: 8595.
  • 27
    Hsu PP, Sabatini DM. Cancer cell metabolism: warburg and beyond. Cell. 2008; 134: 703707.
  • 28
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646674.
  • 29
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324: 10291033.
  • 30
    Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov. 2002; 1: 727730.
  • 31
    Verdine GL, Walensky LD. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. 2007; 13: 72647270.
  • 32
    Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov. 2004; 3: 301317.
  • 33
    Sebolt-Leopold JS. Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin Cancer Res. 2008; 14: 36513656.
  • 34
    Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011; 10: 671684.
  • 35
    Kamb A, Wee S, Lengauer C. Why is cancer drug discovery so difficult? Nat Rev Drug Discov. 2007; 6: 115120.
  • 36
    Hamanaka RB, Chandel NS. Targeting glucose metabolism for cancer therapy. J Exp Med. 2012; 209: 211215.
  • 37
    Warburg O. On the origin of cancer cells. Science. 1956; 123: 309314.
  • 38
    Warburg O, Posener K, Negelein E. On the metabolism of carcinoma cells. Biochem Z. 1924; 152: 309344.
  • 39
    Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011; 27: 441464.
  • 40
    Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010; 20: 5156.
  • 41
    Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell. 2007; 12: 108113.
  • 42
    Iyer NV, Kotch LE, Agani F, Leung, SW,Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α.pdf. Genes Dev. 1998; 12: 149162.
  • 43
    Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999; 15: 551578.
  • 44
    Carmeliet P, Dor Y, Herbert J,Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshet E. Role of HIF-1 in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998; 395: 485490.
  • 45
    Kümmel A, Panke S, Heinemann M. Putative regulatory sites unraveled by network-embedded thermodynamic analysis of metabolome data. Mol Syst Biol. 2006; 2: 2006.0034.
  • 46
    Dang L, White DW, Gross S,Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009; 462: 739744.
  • 47
    Ward PS, Patel J, Wise DR, Abdel-Wahab O,Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17: 225234.
  • 48
    Cobelli C, Toffolo G, Bier DM, Nosadini R. Models to interpret kinetic data in stable isotope tracer studies. Am J Physiol. 1987; 253( 5 Pt 1): E551E564.
  • 49
    Bosner MS, Lange LG, Stenson WF, Ostlund RE. Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res. 1999; 40: 302308.
  • 50
    Hellerstein MK, Christiansen M, Kaempfer S,Kletke C, Wu K, Reid JS, Mulligan K, Hellerstein NS, Shackleton CHL. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J Clin Invest. 1991; 87: 18411852.
  • 51
    Aarsland A, Chinkes D, Wolfe RR. Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man. J Clin Invest. 1996; 98: 20082017.
  • 52
    Bier DM, Arnold KJ, Sherman WR, Holland WH, Holmes WF, Kipnis DM. In-vivo measurement of glucose and alanine metabolism with stable isotopic tracers. Diabetes. 1977; 26: 10051015.
  • 53
    Wolfe RR, Chinkes DL. Isotope Tracers in Metabolic Research: Principles and Practice of Kinetic Analysis, 2nd ed. Hoboken, NJ: Wiley-Liss; 2005.
  • 54
    Nielsen J. Metabolic engineering: techniques for analysis of targets for genetic manipulations. Biotechnol Bioeng. 1998; 58: 125132.
  • 55
    Kelleher JK, Masterson TM. Model equations for condensation biosynthesis using stable isotopes and radioisotopes. Am J Physiol. 1992; 262( 1 Pt 1): E118E125.
  • 56
    Hellerstein MK, Neese R A. Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am J Physiol. 1992; 263( 5 Pt 1): E988E1001.
  • 57
    Kelleher JK, Kharroubi AT, Aldaghlas TA,Shambat IB, Kennedy KA, Holleran AL, Masterson TM. Isotopomer spectral analysis of cholesterol synthesis: applications in human hepatoma cells. Am J Physiol Endocrinol Metab. 1994; 266: E384E395.
  • 58
    Landau BR. Quantifying the contribution of gluconeogenesis to glucose production in fasted human subjects using stable isotopes. Proc Nutr Soc. 1999; 58: 963972.
  • 59
    Pizer ES, Chrest FJ, Digiuseppe JA, Han WF. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res. 1998; 58: 46114615.
  • 60
    Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007; 7: 763777.
  • 61
    Mancuso A, Sharfstein ST, Tucker SN, Clark DS, Blanch HW. Examination of primary metabolic pathways in a murine hybridoma with carbon-13 nuclear magnetic resonance spectroscopy. Biotechnol Bioeng. 1994; 44: 563585.
  • 62
    Mancuso A, Sharfstein ST, Fernandez EJ, Clark DS, Blanch HW. Effect of extracellular glutamine concentration on primary and secondary metabolism of a murine hybridoma: an in vivo 13C nuclear magnetic resonance study. Biotechnol Bioeng. 1998; 57: 172186.
  • 63
    Sharfstein ST, Tucker SN, Mancuso a, Blanch HW, Clark DS. Quantitative in vivo nuclear magnetic resonance studies of hybridoma metabolism. Biotechnol Bioeng. 1994; 43: 10591074.
  • 64
    Zamboni N. 13C metabolic flux analysis in complex systems. Curr Opin Biotechnol. 2011; 22: 103108.
  • 65
    Antoniewicz MR, Kelleher JK, Stephanopoulos G. Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements. Metab Eng. 2006; 8: 324337.
  • 66
    Wiechert W, Siefke C, de Graaf AA, Marx a. Bidirectional reaction steps in metabolic networks. II. Flux estimation and statistical analysis. Biotechnol Bioeng. 1997; 55: 11835.
  • 67
    Araúzo-Bravo M. An improved method for statistical analysis of metabolic flux analysis using isotopomer mapping matrices with analytical expressions. J Biotechnol. 2003; 105: 117133.
  • 68
    Antoniewicz MR, Kelleher JK, Stephanopoulos G. Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab Eng. 2007; 9: 6886.
  • 69
    Wiechert W, Möllney M, Isermann N, Wurzel M, de Graaf AA. Bidirectional reaction steps in metabolic networks. III. Explicit solution and analysis of isotopomer labeling systems. Biotechnol Bioeng. 1999; 66: 6985.
  • 70
    Hiller K, Metallo CM, Kelleher JK, Stephanopoulos G. Nontargeted elucidation of metabolic pathways using stable-isotope tracers and mass spectrometry. Anal Chem. 2010; 82: 66216628.
  • 71
    Metallo CM, Walther JL, Stephanopoulos G. Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J Biotechnol. 2009; 144: 167174.
  • 72
    Walther JL, Metallo CM, Zhang J, Stephanopoulos G. Optimization of (13)C isotopic tracers for metabolic flux analysis in mammalian cells. Metab Eng. 2011; 14: 162171.
  • 73
    Metallo CM, Gameiro PA, Bell EL,Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012; 481: 380384.
  • 74
    Wise DR, Ward PS, Shay JES,Cross JR, Gruber JJ, Sachev UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA. 2011; 108: 1961119616.
  • 75
    Mullen AR, Wheaton WW, Jin ES,Chen P, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012; 481: 385388.
  • 76
    Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW. Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res. 2012; 25: 375383.
  • 77
    Kit S. The Biosynthesis of Free Glycine and Serine by Tumors. Cancer Res. 1955; 15: 715718.
  • 78
    Snell K, Natsumeda Y, Weber G. The modulation of serine metabolism in hepatoma 3924A during different phases of cellular proliferation in culture. Biochem J. 1987; 245: 609612.
  • 79
    Bismut H, Caron M, Coudray-Lucas C, Capeau J. Glucose contribution to nucleic acid base synthesis in proliferating hepatoma cells: a glycine-biosynthesis-mediated pathway. Biochem J. 1995; 308( Pt 3): 761767.
  • 80
    Possemato R, Marks KM, Shaul YD,Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo H, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun Z, Cowley GS, Barretina J, Kalaany NY, Hsu PP,Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011; 476: 346350.
  • 81
    Locasale JW, Grassian AR, Melman T,Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011; 43: 869874.
  • 82
    Gaglio D, Metallo CM, Gameiro PA,Hiller K, Danna LS, Balestrieri C, Alberghina L, Stephanopoulos G, Chiaradonna F. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011; 7: 523: 1–15.
  • 83
    Chiaradonna F, Sacco E, Manzoni R, Giorgio M, Vanoni M, Alberghina L. Ras-dependent carbon metabolism and transformation in mouse fibroblasts. Oncogene. 2006; 25: 53915404.
  • 84
    Gao P, Tchernyshyov I, Chang T,Lee Y, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009; 458: 762765.
  • 85
    Grassian AR, Metallo CM, Coloff JL, Stephanopoulos G, Brugge JS. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 2011; 25: 17161733.
  • 86
    Bonnet S, Archer SL, Allalunis-Turner J,Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11: 3751.
  • 87
    Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008; 99: 989994.
  • 88
    Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci. 2007; 64: 830849.
  • 89
    Le A, Lane AN, Hamaker M,Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJC, Lorkiewicz PK, Higashi RM, Fan TWM, Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012; 15: 110121.
  • 90
    Sutherland RM. Cell and environment interactions in microregions: the multicell spheroid tumor model. Science. 1988; 240: 177184.
  • 91
    Wise DR, DeBerardinis RJ, Mancuso A,Sayed N, Zhang X, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008; 105: 1878218787.
  • 92
    Brahimi-Horn MC, Pouysségur J. Oxygen, a source of life and stress. FEBS Lett. 2007; 581: 35823591.
  • 93
    Kim J, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3: 177185.
  • 94
    Yuneva MO, Fan TWM, Allen TD,Higashi RM, Ferraris DV, Tsukamoto T, Matés JM, Alonso FJ, Wang C, Seo Y, Chen X, Bishop JM. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012; 15: 157170.
  • 95
    Sauer U. Metabolic networks in motion: 13C-based flux analysis. Mol Syst Biol. 2006; 2: 62: 1–10.
  • 96
    Tomlinson IPM, Alam NA, Rowan AJ,Barclay E, Jaeger EEM, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002; 30: 406410.
  • 97
    Hao H-X, Khalimonchuk O, Schraders M,Dephoure N, Bayley J, Kunst H, Devilee P, Cremers CWRJ, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009; 325: 11391142.
  • 98
    Baysal BE, Ferrell RE, Willett-Brozick JE,Lawrence EC, Myssiorel D, Bosch A, van der Mey A, Taschner PEM, Rubinstein WS, Myers EN, Richard CWIII, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000; 287: 848851.