Reverse engineering the cancer metabolic network using flux analysis to understand drivers of human disease

Metabolic Engineering

Volumn 45, Issue , 2018, Pages 95-108

  Badur, Mehmet G ^a   Metallo, Christian M ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cancer; Metabolic flux analysis; Metabolism; Metabolomics; Mitochondria; Stable isotope tracing

Indexed keywords

DISEASES; ISOTOPES; MITOCHONDRIA; PHYSIOLOGY; REVERSE ENGINEERING;

CANCER; CONCEPTUAL FRAMEWORKS; DISEASE MODELS; METABOLIC FLUX ANALYSIS; METABOLIC NETWORK; METABOLIC PHENOTYPE; METABOLOMICS; STABLE ISOTOPES;

METABOLISM;

GLUTAMINE; SERINE; STABLE ISOTOPE;

AMINO ACID METABOLISM; AMINO ACID SYNTHESIS; CANCER MODEL; CARBON METABOLISM; CONCEPTUAL FRAMEWORK; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MALIGNANT NEOPLASM; METABOLIC FLUX ANALYSIS; METABOLISM; METABOLOMICS; NONHUMAN; OXIDATION REDUCTION REACTION; PRIORITY JOURNAL; REVERSE ENGINEERING; REVIEW; TUMOR GROWTH; BIOLOGICAL MODEL; METABOLOME; NEOPLASM;

HUMANS; METABOLOME; MODELS, BIOLOGICAL; NEOPLASMS;

EID: 85037675759     PISSN: 10967176     EISSN: 10967184     Source Type: Journal    
DOI: 10.1016/j.ymben.2017.11.013     Document Type: Review

References (196)

1. Antoniewicz, M.R., Kelleher, J.K., Stephanopoulos, G., Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements. Metab. Eng. 8 (2006), 324–337.
2. Antoniewicz, M.R., Kelleher, J.K., Stephanopoulos, G., Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab. Eng. 9 (2007), 68–86.
3. Badur, M.G., Zhang, H., Metallo, C.M., Enzymatic passaging of human embryonic stem cells alters central carbon metabolism and glycan abundance. Biotechnol. J. 10 (2015), 1600–1611.
4. Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C., von Deimling, A., Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116 (2008), 597–602.
5. Beard, D.A., Liang, S.D., Qian, H., Energy balance for analysis of complex metabolic networks. Biophys. J. 83 (2002), 79–86.
6. Beard, D.A., Qian, H., Thermodynamic-based computational profiling of cellular regulatory control in hepatocyte metabolism. Am. J. Physiol. Endocrinol. Metab. 288 (2005), E633–E644.
7. Ben-Sahra, I., Hoxhaj, G., Ricoult, S.J., Asara, J.M., Manning, B.D., mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351 (2016), 728–733.
8. Ben-Yoseph, O., Kingsley, P.B., Ross, B.D., Metabolic loss of deuterium from isotopically labeled glucose. Magn. Reson. Med. 32 (1994), 405–409.
9. Benjamin, D.I., Li, D.S., Lowe, W., Heuer, T., Kemble, G., Nomura, D.K., Diacylglycerol metabolism and signaling is a driving force underlying FASN inhibitor sensitivity in cancer cells. ACS Chem. Biol. 10 (2015), 1616–1623.
10. Bennett, B.D., Kimball, E.H., Gao, M., Osterhout, R., Van Dien, S.J., Rabinowitz, J.D., Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli. Nat. Chem. Biol. 5 (2009), 593–599.
11. Boroughs, L.K., DeBerardinis, R.J., Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17 (2015), 351–359.
12. Brusselmans, K., De Schrijver, E., Verhoeven, G., Swinnen, J.V., RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 65 (2005), 6719–6725.
13. Buescher, J.M., Antoniewicz, M.R., Boros, L.G., Burgess, S.C., Brunengraber, H., Clish, C.B., DeBerardinis, R.J., Feron, O., Frezza, C., Ghesquiere, B., Gottlieb, E., Hiller, K., Jones, R.G., Kamphorst, J.J., Kibbey, R.G., Kimmelman, A.C., Locasale, J.W., Lunt, S.Y., Maddocks, O.D., Malloy, C., Metallo, C.M., Meuillet, E.J., Munger, J., Noh, K., Rabinowitz, J.D., Ralser, M., Sauer, U., Stephanopoulos, G., St-Pierre, J., Tennant, D.A., Wittmann, C., Vander Heiden, M.G., Vazquez, A., Vousden, K., Young, J.D., Zamboni, N., Fendt, S.M., A roadmap for interpreting (13)C metabolite labeling patterns from cells. Curr. Opin. Biotechnol. 34 (2015), 189–201.
14. Burk, D., Schade, A.L., On respiratory impairment in cancer cells. Science 124 (1956), 270–272.
15. Cancer Genome Atlas Research, N., Weinstein, J.N., Collisson, E.A., Mills, G.B., Shaw, K.R., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., Stuart, J.M., The cancer genome atlas Pan-cancer analysis project. Nat. Genet. 45 (2013), 1113–1120.
16. Cantoni, G.L., S-adenosylmethionine - a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J. Biol. Chem. 204 (1953), 403–416.
17. Cardaci, S., Zheng, L., MacKay, G., van den Broek, N.J., MacKenzie, E.D., Nixon, C., Stevenson, D., Tumanov, S., Bulusu, V., Kamphorst, J.J., Vazquez, A., Fleming, S., Schiavi, F., Kalna, G., Blyth, K., Strathdee, D., Gottlieb, E., Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17 (2015), 1317–1326.
18. Chan, S.M., Thomas, D., Corces-Zimmerman, M.R., Xavy, S., Rastogi, S., Hong, W.J., Zhao, F., Medeiros, B.C., Tyvoll, D.A., Majeti, R., Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21 (2015), 178–184.
19. Chaumeil, M.M., Larson, P.E., Woods, S.M., Cai, L., Eriksson, P., Robinson, A.E., Lupo, J.M., Vigneron, D.B., Nelson, S.J., Pieper, R.O., Phillips, J.J., Ronen, S.M., Hyperpolarized [1–13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma. Cancer Res. 74 (2014), 4247–4257.
20. Cheng, T., Sudderth, J., Yang, C., Mullen, A.R., Jin, E.S., Mates, J.M., DeBerardinis, R.J., Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl. Acad. Sci. USA 108 (2011), 8674–8679.
21. Choi, C., Ganji, S.K., DeBerardinis, R.J., Hatanpaa, K.J., Rakheja, D., Kovacs, Z., Yang, X.L., Mashimo, T., Raisanen, J.M., Marin-Valencia, I., Pascual, J.M., Madden, C.J., Mickey, B.E., Malloy, C.R., Bachoo, R.M., Maher, E.A., 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 18 (2012), 624–629.
22. Commisso, C., Davidson, S.M., Soydaner-Azeloglu, R.G., Parker, S.J., Kamphorst, J.J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J.A., Thompson, C.B., Rabinowitz, J.D., Metallo, C.M., Vander Heiden, M.G., Bar-Sagi, D., Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497 (2013), 633–637.
23. Cordes, T., Metallo, C.M., Tracing insights into human metabolism using chemical engineering approaches. Curr. Opin. Chem. Eng. 14 (2016), 72–81.
24. Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A.S., Sapcariu, S.C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A.N., Hiller, K., Metallo, C.M., Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291 (2016), 14274–14284.
25. Crown, S.B., Ahn, W.S., Antoniewicz, M.R., Rational design of (1)(3)C-labeling experiments for metabolic flux analysis in mammalian cells. BMC Syst. Biol., 6, 2012, 43.
26. Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., Marks, K.M., Prins, R.M., Ward, P.S., Yen, K.E., Liau, L.M., Rabinowitz, J.D., Cantley, L.C., Thompson, C.B., Vander Heiden, M.G., Su, S.M., Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462 (2009), 739–744.
27. Dang, L., Yen, K., Attar, E.C., IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27 (2016), 599–608.
28. Davidson, S.M., Jonas, O., Keibler, M.A., Hou, H.W., Luengo, A., Mayers, J.R., Wyckoff, J., Del Rosario, A.M., Whitman, M., Chin, C.R., Condon, K.J., Lammers, A., Kellersberger, K.A., Stall, B.K., Stephanopoulos, G., Bar-Sagi, D., Han, J., Rabinowitz, J.D., Cima, M.J., Langer, R., Vander Heiden, M.G., Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23 (2017), 235–241.
29. Davidson, S.M., Papagiannakopoulos, T., Olenchock, B.A., Heyman, J.E., Keibler, M.A., Luengo, A., Bauer, M.R., Jha, A.K., O'Brien, J.P., Pierce, K.A., Gui, D.Y., Sullivan, L.B., Wasylenko, T.M., Subbaraj, L., Chin, C.R., Stephanopolous, G., Mott, B.T., Jacks, T., Clish, C.B., Vander Heiden, M.G., Environment impacts the metabolic dependencies of ras-driven non-small cell lung cancer. Cell Metab. 23 (2016), 517–528.
30. Davis, S.R., Stacpoole, P.W., Williamson, J., Kick, L.S., Quinlivan, E.P., Coats, B.S., Shane, B., Bailey, L.B., Gregory, J.F. 3rd, Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am. J. Physiol. Endocrinol. Metab. 286 (2004), E272–E279.
31. DeBerardinis, R.J., Cheng, T., Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29 (2010), 313–324.
32. DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., Thompson, C.B., The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7 (2008), 11–20.
33. DeBerardinis, R.J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., Thompson, C.B., Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. USA 104 (2007), 19345–19350.
34. DeNicola, G.M., Chen, P.H., Mullarky, E., Sudderth, J.A., Hu, Z., Wu, D., Tang, H., Xie, Y., Asara, J.M., Huffman, K.E., Wistuba, I.I., Minna, J.D., DeBerardinis, R.J., Cantley, L.C., NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47 (2015), 1475–1481.
35. Des Rosiers, C., Di Donato, L., Comte, B., Laplante, A., Marcoux, C., David, F., Fernandez, C.A., Brunengraber, H., Isotopomer analysis of citric acid cycle and gluconeogenesis in rat liver. Reversibility of isocitrate dehydrogenase and involvement of ATP-citrate lyase in gluconeogenesis. J. Biol. Chem. 270 (1995), 10027–10036.
36. Divakaruni, A.S., Wallace, M., Buren, C., Martyniuk, K., Andreyev, A.Y., Li, E., Fields, J.A., Cordes, T., Reynolds, I.J., Bloodgood, B.L., Raymond, L.A., Metallo, C.M., Murphy, A.N., Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. J. Cell Biol. 216 (2017), 1091–1105.
37. Divakaruni, A.S., Wiley, S.E., Rogers, G.W., Andreyev, A.Y., Petrosyan, S., Loviscach, M., Wall, E.A., Yadava, N., Heuck, A.P., Ferrick, D.A., Henry, R.R., McDonald, W.G., Colca, J.R., Simon, M.I., Ciaraldi, T.P., Murphy, A.N., Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc. Natl. Acad. Sci. USA 110 (2013), 5422–5427.
38. Ducker, G.S., Chen, L., Morscher, R.J., Ghergurovich, J.M., Esposito, M., Teng, X., Kang, Y., Rabinowitz, J.D., Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 23 (2016), 1140–1153.
39. Eales, K.L., Hollinshead, K.E., Tennant, D.A., Hypoxia and metabolic adaptation of cancer cells. Oncogenesis, 5, 2016, e190.
40. Fan, J., Kamphorst, J.J., Mathew, R., Chung, M.K., White, E., Shlomi, T., Rabinowitz, J.D., Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol. Syst. Biol., 9, 2013, 712.
41. Fan, J., Ye, J., Kamphorst, J.J., Shlomi, T., Thompson, C.B., Rabinowitz, J.D., Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510 (2014), 298–302.
42. Farwell, M.D., Pryma, D.A., Mankoff, D.A., PET/CT imaging in cancer: current applications and future directions. Cancer 120 (2014), 3433–3445.
43. Fendt, S.M., Bell, E.L., Keibler, M.A., Olenchock, B.A., Mayers, J.R., Wasylenko, T.M., Vokes, N.I., Guarente, L., Vander Heiden, M.G., Stephanopoulos, G., Reductive glutamine metabolism is a function of the alpha-ketoglutarate to citrate ratio in cells. Nat. Commun., 4, 2013, 2236.
44. Fiehn, O., Kopka, J., Dormann, P., Altmann, T., Trethewey, R.N., Willmitzer, L., Metabolite profiling for plant functional genomics. Nat. Biotechnol. 18 (2000), 1157–1161.
45. Figueroa, M.E., Abdel-Wahab, O., Lu, C., Ward, P.S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H.F., Tallman, M.S., Sun, Z., Wolniak, K., Peeters, J.K., Liu, W., Choe, S.E., Fantin, V.R., Paietta, E., Lowenberg, B., Licht, J.D., Godley, L.A., Delwel, R., Valk, P.J., Thompson, C.B., Levine, R.L., Melnick, A., Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 18 (2010), 553–567.
46. Fox, J.T., Stover, P.J., Folate-mediated one-carbon metabolism. Vitam. Horm. 79 (2008), 1–44.
47. Frezza, C., Zheng, L., Folger, O., Rajagopalan, K.N., MacKenzie, E.D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I.P., Pollard, P.J., Watson, D.G., Deberardinis, R.J., Shlomi, T., Ruppin, E., Gottlieb, E., Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477 (2011), 225–228.
48. Gameiro, P.A., Laviolette, L.A., Kelleher, J.K., Iliopoulos, O., Stephanopoulos, G., Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J. Biol. Chem. 288 (2013), 12967–12977.
49. Gameiro, P.A., Yang, J., Metelo, A.M., Perez-Carro, R., Baker, R., Wang, Z., Arreola, A., Rathmell, W.K., Olumi, A., Lopez-Larrubia, P., Stephanopoulos, G., Iliopoulos, O., In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 17 (2013), 372–385.
50. Gasparre, G., Porcelli, A.M., Bonora, E., Pennisi, L.F., Toller, M., Iommarini, L., Ghelli, A., Moretti, M., Betts, C.M., Martinelli, G.N., Ceroni, A.R., Curcio, F., Carelli, V., Rugolo, M., Tallini, G., Romeo, G., Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proc. Natl. Acad. Sci. USA 104 (2007), 9001–9006.
51. Gebreselassie, N.A., Antoniewicz, M.R., (13)C-metabolic flux analysis of co-cultures: a novel approach. Metab. Eng. 31 (2015), 132–139.
52. Ghosh, A., Tyson, T., George, S., Hildebrandt, E.N., Steiner, J.A., Madaj, Z., Schulz, E., Machiela, E., McDonald, W.G., Escobar Galvis, M.L., Kordower, J.H., Van Raamsdonk, J.M., Colca, J.R., Brundin, P., Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease. Sci. Transl. Med., 8, 2016, 368ra174.
53. Gopalakrishnan, S., Maranas, C.D., 13C metabolic flux analysis at a genome-scale. Metab. Eng. 32 (2015), 12–22.
54. Grassian, A.R., Metallo, C.M., Coloff, J.L., Stephanopoulos, G., Brugge, J.S., Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 25 (2011), 1716–1733.
55. Grassian, A.R., Parker, S.J., Davidson, S.M., Divakaruni, A.S., Green, C.R., Zhang, X., Slocum, K.L., Pu, M., Lin, F., Vickers, C., Joud-Caldwell, C., Chung, F., Yin, H., Handly, E.D., Straub, C., Growney, J.D., Vander Heiden, M.G., Murphy, A.N., Pagliarini, R., Metallo, C.M., IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 74 (2014), 3317–3331.
56. Gravel, S.P., Hulea, L., Toban, N., Birman, E., Blouin, M.J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., Pollak, M., Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74 (2014), 7521–7533.
57. Gray, L.R., Sultana, M.R., Rauckhorst, A.J., Oonthonpan, L., Tompkins, S.C., Sharma, A., Fu, X., Miao, R., Pewa, A.D., Brown, K.S., Lane, E.E., Dohlman, A., Zepeda-Orozco, D., Xie, J., Rutter, J., Norris, A.W., Cox, J.E., Burgess, S.C., Potthoff, M.J., Taylor, E.B., Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis. Cell Metab. 22 (2015), 669–681.
58. Green, C.R., Wallace, M., Divakaruni, A.S., Phillips, S.A., Murphy, A.N., Ciaraldi, T.P., Metallo, C.M., Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12 (2016), 15–21.
59. Gu, W., Gaeta, X., Sahakyan, A., Chan, A.B., Hong, C.S., Kim, R., Braas, D., Plath, K., Lowry, W.E., Christofk, H.R., Glycolytic metabolism plays a functional role in regulating human pluripotent stem cell state. Cell Stem Cell 19 (2016), 476–490.
60. Gut, P., Verdin, E., The nexus of chromatin regulation and intermediary metabolism. Nature 502 (2013), 489–498.
61. Hackett, S.R., Zanotelli, V.R., Xu, W., Goya, J., Park, J.O., Perlman, D.H., Gibney, P.A., Botstein, D., Storey, J.D., Rabinowitz, J.D., Systems-level analysis of mechanisms regulating yeast metabolic flux. Science, 2016, 354.
62. Hakimi, A.A., Reznik, E., Lee, C.H., Creighton, C.J., Brannon, A.R., Luna, A., Aksoy, B.A., Liu, E.M., Shen, R., Lee, W., Chen, Y., Stirdivant, S.M., Russo, P., Chen, Y.B., Tickoo, S.K., Reuter, V.E., Cheng, E.H., Sander, C., Hsieh, J.J., An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 29 (2016), 104–116.
63. Hale, J.S., Otvos, B., Sinyuk, M., Alvarado, A.G., Hitomi, M., Stoltz, K., Wu, Q., Flavahan, W., Levison, B., Johansen, M.L., Schmitt, D., Neltner, J.M., Huang, P., Ren, B., Sloan, A.E., Silverstein, R.L., Gladson, C.L., DiDonato, J.A., Brown, J.M., McIntyre, T., Hazen, S.L., Horbinski, C., Rich, J.N., Lathia, J.D., Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression. Stem Cells 32 (2014), 1746–1758.
64. Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation. Cell 144 (2011), 646–674.
65. Hatzivassiliou, G., Zhao, F., Bauer, D.E., Andreadis, C., Shaw, A.N., Dhanak, D., Hingorani, S.R., Tuveson, D.A., Thompson, C.B., ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8 (2005), 311–321.
66. Hellerstein, M.K., New stable isotope-mass spectrometric techniques for measuring fluxes through intact metabolic pathways in mammalian systems: introduction of moving pictures into functional genomics and biochemical phenotyping. Metab. Eng. 6 (2004), 85–100.
67. Hensley, C.T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., Wodzak, M., Klimko, C., McMillan, E., Butt, Y., Ni, M., Oliver, D., Torrealba, J., Malloy, C.R., Kernstine, K., Lenkinski, R.E., DeBerardinis, R.J., Metabolic heterogeneity in human lung tumors. Cell 164 (2016), 681–694.
68. Herbig, K., Chiang, E.P., Lee, L.R., Hills, J., Shane, B., Stover, P.J., Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J. Biol. Chem. 277 (2002), 38381–38389.
69. Hochachka, P.W., McClelland, G.B., Cellular metabolic homeostasis during large-scale change in ATP turnover rates in muscles. J. Exp. Biol. 200 (1997), 381–386.
70. Hosios, A.M., Hecht, V.C., Danai, L.V., Johnson, M.O., Rathmell, J.C., Steinhauser, M.L., Manalis, S.R., Vander Heiden, M.G., Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell. 36 (2016), 540–549.
71. Izquierdo-Garcia, J.L., Viswanath, P., Eriksson, P., Cai, L., Radoul, M., Chaumeil, M.M., Blough, M., Luchman, H.A., Weiss, S., Cairncross, J.G., Phillips, J.J., Pieper, R.O., Ronen, S.M., IDH1 mutation induces reprogramming of pyruvate metabolism. Cancer Res. 75 (2015), 2999–3009.
72. Jacobus, W.E., Respiratory control and the integration of heart high-energy phosphate metabolism by mitochondrial creatine kinase. Annu. Rev. Physiol. 47 (1985), 707–725.
73. Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A.L., Kafri, R., Kirschner, M.W., Clish, C.B., Mootha, V.K., Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336 (2012), 1040–1044.
74. Jazmin, L.J., Young, J.D., Isotopically nonstationary 13C metabolic flux analysis. Methods Mol. Biol. 985 (2013), 367–390.
75. Jiang, L., Boufersaoui, A., Yang, C., Ko, B., Rakheja, D., Guevara, G., Hu, Z., DeBerardinis, R.J., Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein. Metab. Eng., 2016.
76. Jiang, L., Shestov, A.A., Swain, P., Yang, C., Parker, S.J., Wang, Q.A., Terada, L.S., Adams, N.D., McCabe, M.T., Pietrak, B., Schmidt, S., Metallo, C.M., Dranka, B.P., Schwartz, B., DeBerardinis, R.J., Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532 (2016), 255–258.
77. Johnson, C.H., Ivanisevic, J., Siuzdak, G., Metabolomics: beyond biomarkers and towards mechanisms. Nat. Rev. Mol. Cell Biol., 2016.
78. Kamphorst, J.J., Nofal, M., Commisso, C., Hackett, S.R., Lu, W., Grabocka, E., Vander Heiden, M.G., Miller, G., Drebin, J.A., Bar-Sagi, D., Thompson, C.B., Rabinowitz, J.D., Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75 (2015), 544–553.
79. Katz, J., Rognstad, R., Kemp, R.G., Isotope discrimination effects in the metabolism of tritiated glucose. J. Biol. Chem. 240 (1965), PC1484–PC1486.
80. King, A., Selak, M.A., Gottlieb, E., Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25 (2006), 4675–4682.
81. Kinnaird, A., Zhao, S., Wellen, K.E., Michelakis, E.D., Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16 (2016), 694–707.
82. Kottakis, F., Nicolay, B.N., Roumane, A., Karnik, R., Gu, H., Nagle, J.M., Boukhali, M., Hayward, M.C., Li, Y.Y., Chen, T., Liesa, M., Hammerman, P.S., Wong, K.K., Hayes, D.N., Shirihai, O.S., Dyson, N.J., Haas, W., Meissner, A., Bardeesy, N., LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539 (2016), 390–395.
83. Kung, H.N., Marks, J.R., Chi, J.T., Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet., 7, 2011, e1002229.
84. Labuschagne, C.F., van den Broek, N.J., Mackay, G.M., Vousden, K.H., Maddocks, O.D., Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7 (2014), 1248–1258.
85. Lackey, D.E., Lynch, C.J., Olson, K.C., Mostaedi, R., Ali, M., Smith, W.H., Karpe, F., Humphreys, S., Bedinger, D.H., Dunn, T.N., Thomas, A.P., Oort, P.J., Kieffer, D.A., Amin, R., Bettaieb, A., Haj, F.G., Permana, P., Anthony, T.G., Adams, S.H., Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am. J. Physiol. Endocrinol. Metab. 304 (2013), E1175–E1187.
86. Lampropoulou, V., Sergushichev, A., Bambouskova, M., Nair, S., Vincent, E.E., Loginicheva, E., Cervantes-Barragan, L., Ma, X., Huang, S.C., Griss, T., Weinheimer, C.J., Khader, S., Randolph, G.J., Pearce, E.J., Jones, R.G., Diwan, A., Diamond, M.S., Artyomov, M.N., Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24 (2016), 158–166.
87. Lane, A.N., Fan, T.W., Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43 (2015), 2466–2485.
88. LaNoue, K.F., Schoolwerth, A.C., Metabolite transport in mitochondria. Annu. Rev. Biochem. 48 (1979), 871–922.
89. Le, A., Lane, A.N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C.J., Slusher, B.S., Zhang, H., Zimmerman, L.J., Liebler, D.C., Slebos, R.J., Lorkiewicz, P.K., Higashi, R.M., Fan, T.W., Dang, C.V., Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 15 (2012), 110–121.
90. Lee, W.N., Boros, L.G., Puigjaner, J., Bassilian, S., Lim, S., Cascante, M., Mass isotopomer study of the nonoxidative pathways of the pentose cycle with [1,2-13C2]glucose. Am. J. Physiol. 274 (1998), E843–E851.
91. Lemons, J.M., Feng, X.J., Bennett, B.D., Legesse-Miller, A., Johnson, E.L., Raitman, I., Pollina, E.A., Rabitz, H.A., Rabinowitz, J.D., Coller, H.A., Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol., 8, 2010, e1000514.
92. Lewis, C.A., Parker, S.J., Fiske, B.P., McCloskey, D., Gui, D.Y., Green, C.R., Vokes, N.I., Feist, A.M., Vander Heiden, M.G., Metallo, C.M., Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell. 55 (2014), 253–263.
93. Lewis, N.E., Schramm, G., Bordbar, A., Schellenberger, J., Andersen, M.P., Cheng, J.K., Patel, N., Yee, A., Lewis, R.A., Eils, R., Konig, R., Palsson, B.O., Large-scale in silico modeling of metabolic interactions between cell types in the human brain. Nat. Biotechnol. 28 (2010), 1279–1285.
94. Liu, L., Shah, S., Fan, J., Park, J.O., Wellen, K.E., Rabinowitz, J.D., Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Nat. Chem. Biol. 12 (2016), 345–352.
95. Locasale, J.W., Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13 (2013), 572–583.
96. Locasale, J.W., Grassian, A.R., Melman, T., Lyssiotis, C.A., Mattaini, K.R., Bass, A.J., Heffron, G., Metallo, C.M., Muranen, T., Sharfi, H., Sasaki, A.T., Anastasiou, D., Mullarky, E., Vokes, N.I., Sasaki, M., Beroukhim, R., Stephanopoulos, G., Ligon, A.H., Meyerson, M., Richardson, A.L., Chin, L., Wagner, G., Asara, J.M., Brugge, J.S., Cantley, L.C., Vander Heiden, M.G., Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43 (2011), 869–874.
97. Lu, C., Ward, P.S., Kapoor, G.S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C.R., Khanin, R., Figueroa, M.E., Melnick, A., Wellen, K.E., O'Rourke, D.M., Berger, S.L., Chan, T.A., Levine, R.L., Mellinghoff, I.K., Thompson, C.B., IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483 (2012), 474–478.
98. Lunt, S.Y., Muralidhar, V., Hosios, A.M., Israelsen, W.J., Gui, D.Y., Newhouse, L., Ogrodzinski, M., Hecht, V., Xu, K., Acevedo, P.N., Hollern, D.P., Bellinger, G., Dayton, T.L., Christen, S., Elia, I., Dinh, A.T., Stephanopoulos, G., Manalis, S.R., Yaffe, M.B., Andrechek, E.R., Fendt, S.M., Vander Heiden, M.G., Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell 57 (2015), 95–107.
99. Lunt, S.Y., Vander Heiden, M.G., Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27 (2011), 441–464.
100. Lussey-Lepoutre, C., Hollinshead, K.E., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.J., Parker, S.J., Janin, M., Martinelli, C., Ottolenghi, C., Metallo, C., Gimenez-Roqueplo, A.P., Favier, J., Tennant, D.A., Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat. Commun., 6, 2015, 8784.
101. Ma, S., Jiang, B., Deng, W., Gu, Z.K., Wu, F.Z., Li, T., Xia, Y., Yang, H., Ye, D., Xiong, Y., Guan, K.L., D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget 6 (2015), 8606–8620.
102. MacKenzie, E.D., Selak, M.A., Tennant, D.A., Payne, L.J., Crosby, S., Frederiksen, C.M., Watson, D.G., Gottlieb, E., Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol. Cell Biol. 27 (2007), 3282–3289.
103. Maddocks, O.D., Berkers, C.R., Mason, S.M., Zheng, L., Blyth, K., Gottlieb, E., Vousden, K.H., Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493 (2013), 542–546.
104. Maddocks, O.D., Labuschagne, C.F., Adams, P.D., Vousden, K.H., Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol. Cell. 61 (2016), 210–221.
105. Maddocks, O.D.K., Athineos, D., Cheung, E.C., Lee, P., Zhang, T., van den Broek, N.J.F., Mackay, G.M., Labuschagne, C.F., Gay, D., Kruiswijk, F., Blagih, J., Vincent, D.F., Campbell, K.J., Ceteci, F., Sansom, O.J., Blyth, K., Vousden, K.H., Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544 (2017), 372–376.
106. Maier, K., Hofmann, U., Bauer, A., Niebel, A., Vacun, G., Reuss, M., Mauch, K., Quantification of statin effects on hepatic cholesterol synthesis by transient (13)C-flux analysis. Metab. Eng. 11 (2009), 292–309.
107. Mayers, J.R., Torrence, M.E., Danai, L.V., Papagiannakopoulos, T., Davidson, S.M., Bauer, M.R., Lau, A.N., Ji, B.W., Dixit, P.D., Hosios, A.M., Muir, A., Chin, C.R., Freinkman, E., Jacks, T., Wolpin, B.M., Vitkup, D., Vander Heiden, M.G., Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353 (2016), 1161–1165.
108. McCloskey, D., Young, J.D., Xu, S., Palsson, B.O., Feist, A.M., Modeling method for increased precision and scope of directly measurable fluxes at a genome-scale. Anal. Chem. 88 (2016), 3844–3852.
109. McCommis, K.S., Chen, Z., Fu, X., McDonald, W.G., Colca, J.R., Kletzien, R.F., Burgess, S.C., Finck, B.N., Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 22 (2015), 682–694.
110. Meiser, J., Tumanov, S., Maddocks, O., Labuschagne, C.F., Athineos, D., Van Den Broek, N., Mackay, G.M., Gottlieb, E., Blyth, K., Vousden, K., Kamphorst, J.J., Vazquez, A., Serine one-carbon catabolism with formate overflow. Sci. Adv., 2, 2016, e1601273.
111. Mentch, S.J., Mehrmohamadi, M., Huang, L., Liu, X., Gupta, D., Mattocks, D., Gomez Padilla, P., Ables, G., Bamman, M.M., Thalacker-Mercer, A.E., Nichenametla, S.N., Locasale, J.W., Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22 (2015), 861–873.
112. Metallo, C.M., Gameiro, P.A., Bell, E.L., Mattaini, K.R., Yang, J., Hiller, K., Jewell, C.M., Johnson, Z.R., Irvine, D.J., Guarente, L., Kelleher, J.K., Vander Heiden, M.G., Iliopoulos, O., Stephanopoulos, G., Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481 (2012), 380–384.
113. Metallo, C.M., Vander Heiden, M.G., Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev. 24 (2010), 2717–2722.
114. Metallo, C.M., Walther, J.L., Stephanopoulos, G., Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J. Biotechnol. 144 (2009), 167–174.
115. Mews, P., Donahue, G., Drake, A.M., Luczak, V., Abel, T., Berger, S.L., Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546 (2017), 381–386.
116. Milgraum, L.Z., Witters, L.A., Pasternack, G.R., Kuhajda, F.P., Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin. Cancer Res. 3 (1997), 2115–2120.
117. Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M., Motohashi, H., Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22 (2012), 66–79.
118. Muir, A., Danai, L.V., Gui, D.Y., Waingarten, C.Y., Lewis, C.A., Vander Heiden, M.G., Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife, 2017, 6.
119. Mullen, A.R., Hu, Z., Shi, X., Jiang, L., Boroughs, L.K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L.B., Linehan, W.M., Chandel, N.S., DeBerardinis, R.J., Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7 (2014), 1679–1690.
120. Mullen, A.R., Wheaton, W.W., Jin, E.S., Chen, P.H., Sullivan, L.B., Cheng, T., Yang, Y., Linehan, W.M., Chandel, N.S., DeBerardinis, R.J., Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481 (2012), 385–388.
121. Munger, J., Bennett, B.D., Parikh, A., Feng, X.J., McArdle, J., Rabitz, H.A., Shenk, T., Rabinowitz, J.D., Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat. Biotechnol. 26 (2008), 1179–1186.
122. Nagrath, D., Avila-Elchiver, M., Berthiaume, F., Tilles, A.W., Messac, A., Yarmush, M.L., Integrated energy and flux balance based multiobjective framework for large-scale metabolic networks. Ann. Biomed. Eng. 35 (2007), 863–885.
123. Nanchen, A., Fuhrer, T., Sauer, U., Determination of metabolic flux ratios from 13C-experiments and gas chromatography-mass spectrometry data: protocol and principles. Methods Mol. Biol. 358 (2007), 177–197.
124. Nath, A., Li, I., Roberts, L.R., Chan, C., Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci. Rep., 5, 2015, 14752.
125. Nilsson, R., Jain, M., Madhusudhan, N., Sheppard, N.G., Strittmatter, L., Kampf, C., Huang, J., Asplund, A., Mootha, V.K., Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun., 5, 2014, 3128.
126. Noh, K., Gronke, 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. 129 (2007), 249–267.
127. Noh, K., Wiechert, W., Experimental design principles for isotopically instationary 13C labeling experiments. Biotechnol. Bioeng. 94 (2006), 234–251.
128. Okazaki, A., Gameiro, P.A., Christodoulou, D., Laviollette, L., Schneider, M., Chaves, F., Stemmer-Rachamimov, A., Yazinski, S.A., Lee, R., Stephanopoulos, G., Zou, L., Iliopoulos, O., Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. J. Clin. Investig. 127 (2017), 1631–1645.
129. Park, J.O., Rubin, S.A., Xu, Y.F., Amador-Noguez, D., Fan, J., Shlomi, T., Rabinowitz, J.D., Metabolite concentrations, fluxes and free energies imply efficient enzyme usage. Nat. Chem. Biol. 12 (2016), 482–489.
130. Park, T.J., Reznick, J., Peterson, B.L., Blass, G., Omerbasic, D., Bennett, N.C., Kuich, P., Zasada, C., Browe, B.M., Hamann, W., Applegate, D.T., Radke, M.H., Kosten, T., Lutermann, H., Gavaghan, V., Eigenbrod, O., Begay, V., Amoroso, V.G., Govind, V., Minshall, R.D., Smith, E.S.J., Larson, J., Gotthardt, M., Kempa, S., Lewin, G.R., Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356 (2017), 307–311.
131. Parker, S.J., Metallo, C.M., Metabolic consequences of oncogenic IDH mutations. Pharmacol. Ther. 152 (2015), 54–62.
132. Parker, S.J., Metallo, C.M., Chasing one-carbon units to understand the role of serine in epigenetics. Mol. Cell 61 (2016), 185–186.
133. Pascual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, C.S., Berenguer, A., Prats, N., Toll, A., Hueto, J.A., Bescos, C., Di Croce, L., Benitah, S.A., Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541 (2017), 41–45.
134. Pavlova, N.N., Thompson, C.B., The emerging hallmarks of cancer metabolism. Cell Metab. 23 (2016), 27–47.
135. Piskounova, E., Agathocleous, M., Murphy, M.M., Hu, Z., Huddlestun, S.E., Zhao, Z., Leitch, A.M., Johnson, T.M., DeBerardinis, R.J., Morrison, S.J., Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527 (2015), 186–191.
136. Possemato, R., Marks, K.M., Shaul, Y.D., Pacold, M.E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.K., Jang, H.G., Jha, A.K., Chen, W.W., Barrett, F.G., Stransky, N., Tsun, Z.Y., Cowley, G.S., Barretina, J., Kalaany, N.Y., Hsu, P.P., Ottina, K., Chan, A.M., Yuan, B., Garraway, L.A., Root, D.E., Mino-Kenudson, M., Brachtel, E.F., Driggers, E.M., Sabatini, D.M., Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476 (2011), 346–350.
137. Previs, S.F., McLaren, D.G., Wang, S.P., Stout, S.J., Zhou, H., Herath, K., Shah, V., Miller, P.L., Wilsie, L., Castro-Perez, J., Johns, D.G., Cleary, M.A., Roddy, T.P., New methodologies for studying lipid synthesis and turnover: looking backwards to enable moving forwards. Biochim. Biophys. Acta 1842 (2014), 402–413.
138. Quek, L.E., Wittmann, C., Nielsen, L.K., Kromer, J.O., OpenFLUX: efficient modelling software for 13C-based metabolic flux analysis. Microb. Cell Fact., 8, 2009, 25.
139. Rendina, A.R., Hermes, J.D., Cleland, W.W., Use of multiple isotope effects to study the mechanism of 6-phosphogluconate dehydrogenase. Biochemistry 23 (1984), 6257–6262.
140. Rodrigues, T.B., Serrao, E.M., Kennedy, B.W., Hu, D.E., Kettunen, M.I., Brindle, K.M., Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose. Nat. Med. 20 (2014), 93–97.
141. Ruhl, M., Le Coq, D., Aymerich, S., Sauer, U., 13C-flux analysis reveals NADPH-balancing transhydrogenation cycles in stationary phase of nitrogen-starving Bacillus subtilis. J. Biol. Chem. 287 (2012), 27959–27970.
142. Samanta, D., Park, Y., Andrabi, S.A., Shelton, L.M., Gilkes, D.M., Semenza, G.L., PHGDH expression is required for mitochondrial redox homeostasis, breast cancer stem cell maintenance, and lung metastasis. Cancer Res. 76 (2016), 4430–4442.
143. Sauer, U., High-throughput phenomics: experimental methods for mapping fluxomes. Curr. Opin. Biotechnol. 15 (2004), 58–63.
144. Sauer, U., Metabolic networks in motion: 13C-based flux analysis. Mol. Syst. Biol., 2, 2006, 62.
145. Schafer, Z.T., Grassian, A.R., Song, L., Jiang, Z., Gerhart-Hines, Z., Irie, H.Y., Gao, S., Puigserver, P., Brugge, J.S., Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461 (2009), 109–113.
146. Schell, J.C., Olson, K.A., Jiang, L., Hawkins, A.J., Van Vranken, J.G., Xie, J., Egnatchik, R.A., Earl, E.G., DeBerardinis, R.J., Rutter, J., A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell 56 (2014), 400–413.
147. Selak, M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D.G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B., Gottlieb, E., Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7 (2005), 77–85.
148. Sellers, K., Fox, M.P., Bousamra, M. 2nd, Slone, S.P., Higashi, R.M., Miller, D.M., Wang, Y., Yan, J., Yuneva, M.O., Deshpande, R., Lane, A.N., Fan, T.W., Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J. Clin. Investig. 125 (2015), 687–698.
149. Shin, C.S., Mishra, P., Watrous, J.D., Carelli, V., D'Aurelio, M., Jain, M., Chan, D.C., The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat. Commun., 8, 2017, 15074.
150. Sousa, C.M., Biancur, D.E., Wang, X., Halbrook, C.J., Sherman, M.H., Zhang, L., Kremer, D., Hwang, R.F., Witkiewicz, A.K., Ying, H., Asara, J.M., Evans, R.M., Cantley, L.C., Lyssiotis, C.A., Kimmelman, A.C., Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536 (2016), 479–483.
151. Starai, V.J., Celic, I., Cole, R.N., Boeke, J.D., Escalante-Semerena, J.C., Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 298 (2002), 2390–2392.
152. Stephanopoulos, G., Metabolic fluxes and metabolic engineering. Metab. Eng. 1 (1999), 1–11.
153. Stephanopoulos, G., Aristidou, A.A., Nielsen, J.H., Metabolic Engineering: Principles and Methodologies. 1998, Academic Press, San Diego.
154. Stincone, A., Prigione, A., Cramer, T., Wamelink, M.M., Campbell, K., Cheung, E., Olin-Sandoval, V., Gruning, N., Kruger, A., Tauqeer Alam, M., Keller, M.A., Breitenbach, M., Brindle, K.M., Rabinowitz, J.D., Ralser, M., The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc., 2014.
155. Su, X., Wellen, K.E., Rabinowitz, J.D., Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30 (2016), 52–60.
156. Svensson, R.U., Parker, S.J., Eichner, L.J., Kolar, M.J., Wallace, M., Brun, S.N., Lombardo, P.S., Van Nostrand, J.L., Hutchins, A., Vera, L., Gerken, L., Greenwood, J., Bhat, S., Harriman, G., Westlin, W.F., Harwood, H.J. Jr., Saghatelian, A., Kapeller, R., Metallo, C.M., Shaw, R.J., Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22 (2016), 1108–1119.
157. Tardito, S., Oudin, A., Ahmed, S.U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P.O., Weinstock, A., Wagner, A., Lindsay, S.L., Hock, A.K., Barnett, S.C., Ruppin, E., Morkve, S.H., Lund-Johansen, M., Chalmers, A.J., Bjerkvig, R., Niclou, S.P., Gottlieb, E., Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat. Cell Biol. 17 (2015), 1556–1568.
158. Tateishi, K., Wakimoto, H., Iafrate, A.J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., He, T., Shi, X., Gerszten, R.E., Zhang, Y., Yeh, J.R., Curry, W.T., Zhao, D., Sundaram, S., Nigim, F., Koerner, M.V., Ho, Q., Fisher, D.E., Roider, E.M., Kemeny, L.V., Samuels, Y., Flaherty, K.T., Batchelor, T.T., Chi, A.S., Cahill, D.P., Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell. 28 (2015), 773–784.
159. Tibbetts, A.S., Appling, D.R., Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30 (2010), 57–81.
160. Turcan, S., Rohle, D., Goenka, A., Walsh, L.A., Fang, F., Yilmaz, E., Campos, C., Fabius, A.W., Lu, C., Ward, P.S., Thompson, C.B., Kaufman, A., Guryanova, O., Levine, R., Heguy, A., Viale, A., Morris, L.G., Huse, J.T., Mellinghoff, I.K., Chan, T.A., IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483 (2012), 479–483.
161. Vacanti, N.M., Divakaruni, A.S., Green, C.R., Parker, S.J., Henry, R.R., Ciaraldi, T.P., Murphy, A.N., Metallo, C.M., Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol. Cell 56 (2014), 425–435.
162. Vacanti, N.M., Metallo, C.M., Exploring metabolic pathways that contribute to the stem cell phenotype. Biochim. Biophys. Acta 1830 (2013), 2361–2369.
163. Vander Heiden, M.G., DeBerardinis, R.J., Understanding the intersections between metabolism and cancer biology. Cell 168 (2017), 657–669.
164. Vazquez, A., Markert, E.K., Oltvai, Z.N., Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS One, 6, 2011, e25881.
165. Venneti, S., Dunphy, M.P., Zhang, H., Pitter, K.L., Zanzonico, P., Campos, C., Carlin, S.D., La Rocca, G., Lyashchenko, S., Ploessl, K., Rohle, D., Omuro, A.M., Cross, J.R., Brennan, C.W., Weber, W.A., Holland, E.C., Mellinghoff, I.K., Kung, H.F., Lewis, J.S., Thompson, C.B., Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci. Transl. Med., 7, 2015, 274ra17.
166. Wang, Q., Zhang, Y., Yang, C., Xiong, H., Lin, Y., Yao, J., Li, H., Xie, L., Zhao, W., Yao, Y., Ning, Z.B., Zeng, R., Xiong, Y., Guan, K.L., Zhao, S., Zhao, G.P., Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327 (2010), 1004–1007.
167. Warburg, O., On the origin of cancer cells. Science 123 (1956), 309–314.
168. Warburg, O., Wind, F., Negelein, E., The metabolism of tumors in the body. J. Gen. Physiol. 8 (1927), 519–530.
169. Weinberg, F., Chandel, N.S., Mitochondrial metabolism and cancer. Ann. N. Y. Acad. Sci. 1177 (2009), 66–73.
170. Weinberg, F., Hamanaka, R., Wheaton, W.W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G.M., Budinger, G.R., Chandel, N.S., Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA 107 (2010), 8788–8793.
171. Weinhouse, S., On respiratory impairment in cancer cells. Science 124 (1956), 267–269.
172. Weitzel, M., Noh, K., Dalman, T., Niedenfuhr, S., Stute, B., Wiechert, W., 13CFLUX2–high-performance software suite for (13)C-metabolic flux analysis. Bioinformatics 29 (2013), 143–145.
173. Wellen, K.E., Hatzivassiliou, G., Sachdeva, U.M., Bui, T.V., Cross, J.R., Thompson, C.B., ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324 (2009), 1076–1080.
174. Wellen, K.E., Lu, C., Mancuso, A., Lemons, J.M., Ryczko, M., Dennis, J.W., Rabinowitz, J.D., Coller, H.A., Thompson, C.B., The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 24 (2010), 2784–2799.
175. Wiechert, W., 13C metabolic flux analysis. Metab. Eng. 3 (2001), 195–206.
176. Wiechert, W., The thermodynamic meaning of metabolic exchange fluxes. Biophys. J. 93 (2007), 2255–2264.
177. Wiechert, W., Noh, K., Isotopically non-stationary metabolic flux analysis: complex yet highly informative. Curr. Opin. Biotechnol. 24 (2013), 979–986.
178. Wise, D.R., Ward, P.S., Shay, J.E., Cross, J.R., Gruber, J.J., Sachdeva, U.M., Platt, J.M., DeMatteo, R.G., Simon, M.C., Thompson, C.B., Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. USA 108 (2011), 19611–19616.
179. Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., Zhao, S., Ye, D., Xiong, Y., Guan, K.L., Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26 (2012), 1326–1338.
180. Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.H., Ito, S., Yang, C., Wang, P., Xiao, M.T., Liu, L.X., Jiang, W.Q., Liu, J., Zhang, J.Y., Wang, B., Frye, S., Zhang, Y., Xu, Y.H., Lei, Q.Y., Guan, K.L., Zhao, S.M., Xiong, Y., Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19 (2011), 17–30.
181. Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G.J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K.W., Velculescu, V.E., Vogelstein, B., Bigner, D.D., IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360 (2009), 765–773.
182. Yang, C., Ko, B., Hensley, C.T., Jiang, L., Wasti, A.T., Kim, J., Sudderth, J., Calvaruso, M.A., Lumata, L., Mitsche, M., Rutter, J., Merritt, M.E., DeBerardinis, R.J., Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol. Cell 56 (2014), 414–424.
183. Yang, L., Achreja, A., Yeung, T.L., Mangala, L.S., Jiang, D., Han, C., Baddour, J., Marini, J.C., Ni, J., Nakahara, R., Wahlig, S., Chiba, L., Kim, S.H., Morse, J., Pradeep, S., Nagaraja, A.S., Haemmerle, M., Kyunghee, N., Derichsweiler, M., Plackemeier, T., Mercado-Uribe, I., Lopez-Berestein, G., Moss, T., Ram, P.T., Liu, J., Lu, X., Mok, S.C., Sood, A.K., Nagrath, D., Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab. 24 (2016), 685–700.
184. Yao, C.H., Fowle-Grider, R., Mahieu, N.G., Liu, G.Y., Chen, Y.J., Wang, R., Singh, M., Potter, G.S., Gross, R.W., Schaefer, J., Johnson, S.L., Patti, G.J., Exogenous fatty acids are the preferred source of membrane lipids in proliferating fibroblasts. Cell Chem. Biol. 23 (2016), 483–493.
185. Ye, J., Fan, J., Venneti, S., Wan, Y.W., Pawel, B.R., Zhang, J., Finley, L.W., Lu, C., Lindsten, T., Cross, J.R., Qing, G., Liu, Z., Simon, M.C., Rabinowitz, J.D., Thompson, C.B., Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4 (2014), 1406–1417.
186. Yoo, H., Antoniewicz, M.R., Stephanopoulos, G., Kelleher, J.K., Quantifying reductive carboxylation flux of glutamine to lipid in a brown adipocyte cell line. J. Biol. Chem. 283 (2008), 20621–20627.
187. Young, J.D., INCA: a computational platform for isotopically non-stationary metabolic flux analysis. Bioinformatics 30 (2014), 1333–1335.
188. Young, J.D., Shastri, A.A., Stephanopoulos, G., Morgan, J.A., Mapping photoautotrophic metabolism with isotopically nonstationary (13)C flux analysis. Metab. Eng. 13 (2011), 656–665.
189. Young, J.D., Walther, J.L., Antoniewicz, M.R., Yoo, H., Stephanopoulos, G., An elementary metabolite unit (EMU) based method of isotopically nonstationary flux analysis. Biotechnol. Bioeng. 99 (2008), 686–699.
190. Yuan, J., Bennett, B.D., Rabinowitz, J.D., Kinetic flux profiling for quantitation of cellular metabolic fluxes. Nat. Protoc. 3 (2008), 1328–1340.
191. Zamboni, N., 13C metabolic flux analysis in complex systems. Curr. Opin. Biotechnol. 22 (2011), 103–108.
192. Zamboni, N., Fischer, E., Sauer, U., FiatFlux–a software for metabolic flux analysis from 13C-glucose experiments. BMC Bioinform., 6, 2005, 209.
193. Zhang, H., Badur, M.G., Divakaruni, A.S., Parker, S.J., Jager, C., Hiller, K., Murphy, A.N., Metallo, C.M., Distinct metabolic states can support self-renewal and lipogenesis in human pluripotent stem cells under different culture conditions. Cell Rep. 16 (2016), 1536–1547.
194. Zhang, J., Fan, J., Venneti, S., Cross, J.R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E.H., Judkins, A.R., Pawel, B., Baggs, J., Cherry, S., Rabinowitz, J.D., Thompson, C.B., Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56 (2014), 205–218.
195. Zhang, W.C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B.S., Sun, L.L., Tai, B.C., Nga, M.E., Bhakoo, K.K., Jayapal, S.R., Nichane, M., Yu, Q., Ahmed, D.A., Tan, C., Sing, W.P., Tam, J., Thirugananam, A., Noghabi, M.S., Pang, Y.H., Ang, H.S., Mitchell, W., Robson, P., Kaldis, P., Soo, R.A., Swarup, S., Lim, E.H., Lim, B., Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148 (2012), 259–272.
196. Zhao, S., Torres, A., Henry, R.A., Trefely, S., Wallace, M., Lee, J.V., Carrer, A., Sengupta, A., Campbell, S.L., Kuo, Y.M., Frey, A.J., Meurs, N., Viola, J.M., Blair, I.A., Weljie, A.M., Metallo, C.M., Snyder, N.W., Andrews, A.J., Wellen, K.E., ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 17 (2016), 1037–1052.