{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T20:56:51Z","timestamp":1793393811840,"version":"4.5.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM007287"],"award-info":[{"award-number":["T32-GM007287"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MIT Koch Graduate Fellowship"},{"DOI":"10.13039\/100001033","name":"Jane Coffin Childs Memorial Fund for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R35CA242379"],"award-info":[{"award-number":["R35CA242379"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA201276"],"award-info":[{"award-number":["R01CA201276"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA014051"],"award-info":[{"award-number":["P30CA014051"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009730","name":"EIF | Stand Up To Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009730","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005979","name":"Lustgarten Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005979","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Faculty Scholars Grant"],"award-info":[{"award-number":["Faculty Scholars Grant"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Ludwig Center at MIT, the MIT Center for Precision Cancer Medicine, the Emerald Foundation","id":[{"id":"https:\/\/ror.org\/031tb8x29","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Metab"],"DOI":"10.1038\/s42255-021-00486-5","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T12:02:31Z","timestamp":1637323351000},"page":"1500-1511","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Methionine synthase is essential for cancer cell proliferation in physiological folate environments"],"prefix":"10.1038","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5765-0459","authenticated-orcid":false,"given":"Mark R.","family":"Sullivan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia M.","family":"Darnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montana F.","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenzin","family":"Kunchok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Joesch-Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew G.","family":"Rees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5117-5586","authenticated-orcid":false,"given":"Jennifer A.","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1787-5084","authenticated-orcid":false,"given":"Caroline A.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-4192","authenticated-orcid":false,"given":"Matthew G.","family":"Vander Heiden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"486_CR1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1096\/fasebj.10.4.8647346","volume":"10","author":"PK Chiang","year":"1996","unstructured":"Chiang, P. K. et al. S-adenosylmethionine and methylation. FASEB J. 10, 471\u2013480 (1996).","journal-title":"FASEB J."},{"key":"486_CR2","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1093\/nar\/gkv047","volume":"43","author":"AN Lane","year":"2015","unstructured":"Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466\u20132485 (2015).","journal-title":"Nucleic Acids Res."},{"key":"486_CR3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","volume":"25","author":"GS Ducker","year":"2017","unstructured":"Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27\u201342 (2017).","journal-title":"Cell Metab."},{"key":"486_CR4","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1017\/S0007114515001142","volume":"113","author":"CM Pfeiffer","year":"2015","unstructured":"Pfeiffer, C. M. et al. Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2. Br. J. Nutr. 113, 1965\u20131977 (2015).","journal-title":"Br. J. Nutr."},{"key":"486_CR5","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1749-6632.1971.tb46996.x","volume":"186","author":"ID Goldman","year":"1971","unstructured":"Goldman, I. D. The characteristics of the membrane transport of amethopterin and the naturally occurring folates. Ann. NY Acad. Sci. 186, 400\u2013422 (1971).","journal-title":"Ann. NY Acad. Sci."},{"key":"486_CR6","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.molcel.2019.05.006","volume":"75","author":"C Ritchie","year":"2019","unstructured":"Ritchie, C., Cordova, A. F., Hess, G. T., Bassik, M. C. & Li, L. SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Mol. Cell 75, 372\u2013381 (2019).","journal-title":"Mol. Cell"},{"key":"486_CR7","doi-asserted-by":"publisher","unstructured":"Muir, A., Danai, L. V. & Vander Heiden, M. G. Microenvironmental regulation of cancer cell metabolism: implications for experimental design and translational studies. Dis. Model. Mech. https:\/\/doi.org\/10.1242\/dmm.035758 (2018).","DOI":"10.1242\/dmm.035758"},{"key":"486_CR8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nrg.2017.74","volume":"19","author":"G Rancati","year":"2018","unstructured":"Rancati, G., Moffat, J., Typas, A. & Pavelka, N. Emerging and evolving concepts in gene essentiality. Nat. Rev. Genet. 19, 34\u201349 (2018).","journal-title":"Nat. Rev. Genet."},{"key":"486_CR9","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1096\/fasebj.4.5.2407589","volume":"4","author":"RV Banerjee","year":"1990","unstructured":"Banerjee, R. V. & Matthews, R. G. Cobalamin-dependent methionine synthase. FASEB J. 4, 1450\u20131459 (1990).","journal-title":"FASEB J."},{"key":"486_CR10","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/MCO.0b013e328333d157","volume":"13","author":"PJ Stover","year":"2010","unstructured":"Stover, P. J. Vitamin B12 and older adults. Curr. Opin. Clin. Nutr. Metab. Care 13, 24\u201327 (2010).","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"486_CR11","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1182\/blood.V66.3.479.479","volume":"66","author":"I Chanarin","year":"1985","unstructured":"Chanarin, I., Deacon, R., Lumb, M., Muir, M. & Perry, J. Cobalamin-folate interrelations: a critical review. Blood 66, 479\u2013489 (1985).","journal-title":"Blood"},{"key":"486_CR12","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1016\/S0021-9258(18)34896-8","volume":"257","author":"K Fujii","year":"1982","unstructured":"Fujii, K., Nagasaki, T. & Huennekens, F. M. Accumulation of 5-methyltetrahydrofolate in cobalamin-deficient L1210 mouse leukemia cells. J. Biol. Chem. 257, 2144\u20132146 (1982).","journal-title":"J. Biol. Chem."},{"key":"486_CR13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/sj.cdd.4400225","volume":"4","author":"PR Walker","year":"1997","unstructured":"Walker, P. R. et al. Induction of apoptosis in neoplastic cells by depletion of vitamin B12. Cell Death Differ. 4, 233\u2013241 (1997).","journal-title":"Cell Death Differ."},{"key":"486_CR14","first-page":"4015","volume":"57","author":"GR McLean","year":"1997","unstructured":"McLean, G. R. et al. Cobalamin analogues modulate the growth of leukemia cells in vitro. Cancer Res. 57, 4015\u20134022 (1997).","journal-title":"Cancer Res."},{"key":"486_CR15","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1365-2141.1971.tb07066.x","volume":"20","author":"JJ Corcino","year":"1971","unstructured":"Corcino, J. J., Zalusky, R., Greenberg, M. & Herbert, V. Coexistence of pernicious anaemia and chronic myeloid leukaemia: an experiment of nature involving vitamin BI2 metabolism. Br. J. Haematol. 20, 511 (1971).","journal-title":"Br. J. Haematol."},{"key":"486_CR16","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1056\/NEJM196302072680607","volume":"268","author":"DW Eastwood","year":"1963","unstructured":"Eastwood, D. W., Green, C. D., Lambdin, M. A. & Gardner, R. Effect of nitrous oxide on the white-cell count in leukemia. N. Engl. J. Med. 268, 297\u2013299 (1963).","journal-title":"N. Engl. J. Med."},{"key":"486_CR17","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/ajh.2830300212","volume":"30","author":"K Ikeda","year":"1989","unstructured":"Ikeda, K. et al. Antileukemic effect of nitrous oxide in a patient with chronic myelogenous leukemia. Am. J. Hematol. 30, 114 (1989).","journal-title":"Am. J. Hematol."},{"key":"486_CR18","doi-asserted-by":"crossref","first-page":"4600","DOI":"10.1182\/blood.V89.12.4600","volume":"89","author":"JH Matthews","year":"1997","unstructured":"Matthews, J. H. Cyanocobalamin [c-lactam] inhibits vitamin B12 and causes cytotoxicity in HL60 cells: methionine protects cells completely. Blood 89, 4600\u20134607 (1997).","journal-title":"Blood"},{"key":"486_CR19","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/jcp.1041490222","volume":"149","author":"RG Liteplo","year":"1991","unstructured":"Liteplo, R. G., Hipwell, S. E., Rosenblatt, D. S., Sillaots, S. & Lue-Shing, H. Changes in cobalamin metabolism are associated with the altered methionine auxotrophy of highly growth autonomous human melanoma cells. J. Cell. Physiol. 149, 332\u2013338 (1991).","journal-title":"J. Cell. Physiol."},{"key":"486_CR20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1172\/JCI111948","volume":"76","author":"GR Boss","year":"1985","unstructured":"Boss, G. R. Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts. J. Clin. Invest. 76, 213\u2013218 (1985).","journal-title":"J. Clin. Invest."},{"key":"486_CR21","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/0304-4165(83)90345-8","volume":"756","author":"M Lumb","year":"1983","unstructured":"Lumb, M. et al. Effects of nitrous oxide-induced inactivation of cobalamin on methionine and S-adenosylmethionine metabolism in the rat. Biochim. Biophys. Acta 756, 354\u2013359 (1983).","journal-title":"Biochim. Biophys. Acta"},{"key":"486_CR22","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/0024-3205(82)90039-X","volume":"31","author":"J van der Westhuyzen","year":"1982","unstructured":"van der Westhuyzen, J., Fernandes-Costa, F. & Metz, J. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates. Life Sci. 31, 2001\u20132010 (1982).","journal-title":"Life Sci."},{"key":"486_CR23","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0140-6736(81)90649-8","volume":"2","author":"JM Scott","year":"1981","unstructured":"Scott, J. M., Dinn, J. J., Wilson, P. & Weir, D. G. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 2, 334\u2013337 (1981).","journal-title":"Lancet"},{"key":"486_CR24","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","volume":"483","author":"J Barretina","year":"2012","unstructured":"Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603\u2013607 (2012).","journal-title":"Nature"},{"key":"486_CR25","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/bjc.2017.11","volume":"116","author":"MF Hansen","year":"2017","unstructured":"Hansen, M. F., Jensen, S. O., Fuchtbauer, E. M. & Martensen, P. M. High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Br. J. Cancer 116, 752\u2013761 (2017).","journal-title":"Br. J. Cancer"},{"key":"486_CR26","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1126\/science.106.2764.619","volume":"106","author":"S Farber","year":"1947","unstructured":"Farber, S. et al. The action of pteroylglutamic conjugates on man. Science 106, 619\u2013621 (1947).","journal-title":"Science"},{"key":"486_CR27","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1056\/NEJM194806032382301","volume":"238","author":"S Farber","year":"1948","unstructured":"Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F. & Wolff, J. A. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteryl-glutamic acid (aminopterin). N. Engl. J. Med. 238, 787\u2013793 (1948).","journal-title":"N. Engl. J. Med."},{"key":"486_CR28","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/nbt.3460","volume":"34","author":"C Yu","year":"2016","unstructured":"Yu, C. et al. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat. Biotechnol. 34, 419\u2013423 (2016).","journal-title":"Nat. Biotechnol."},{"key":"486_CR29","doi-asserted-by":"crossref","first-page":"E4095","DOI":"10.1073\/pnas.1619582114","volume":"114","author":"AM Palmer","year":"2017","unstructured":"Palmer, A. M., Kamynina, E., Field, M. S. & Stover, P. J. Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability. Proc. Natl Acad. Sci. USA 114, E4095\u2013E4102 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"486_CR30","doi-asserted-by":"publisher","unstructured":"Chen, L., Ducker, G. S., Lu, W., Teng, X. & Rabinowitz, J. D. An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate. Anal. Bioanal. Chem. https:\/\/doi.org\/10.1007\/s00216-017-0514-4 (2017).","DOI":"10.1007\/s00216-017-0514-4"},{"key":"486_CR31","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1021\/bi00122a036","volume":"31","author":"P Stover","year":"1992","unstructured":"Stover, P. & Schirch, V. Evidence for the accumulation of a stable intermediate in the nonenzymatic hydrolysis of 5,10-methenyltetrahydropteroylglutamate to 5-formyltetrahydropteroylglutamate. Biochemistry 31, 2148\u20132155 (1992).","journal-title":"Biochemistry"},{"key":"486_CR32","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.celrep.2014.04.045","volume":"7","author":"CF Labuschagne","year":"2014","unstructured":"Labuschagne, C. F., van den Broek, N. J., Mackay, G. M., Vousden, K. H. & Maddocks, O. D. K. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7, 1248\u20131258 (2014).","journal-title":"Cell Rep."},{"key":"486_CR33","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-00854-w","volume":"7","author":"K Misselbeck","year":"2017","unstructured":"Misselbeck, K. et al. A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis. Sci. Rep. 7, 797 (2017).","journal-title":"Sci. Rep."},{"key":"486_CR34","doi-asserted-by":"crossref","first-page":"3904","DOI":"10.1016\/S0021-9258(19)43819-2","volume":"248","author":"G Bjursell","year":"1973","unstructured":"Bjursell, G. & Reichard, P. Effects of thymidine on deoxyribonucleoside triphosphate pools and deoxyribonucleic acid synthesis in chinese hamster ovary cells. J. Biol. Chem. 248, 3904\u20133909 (1973).","journal-title":"J. Biol. Chem."},{"key":"486_CR35","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41586-019-1437-3","volume":"572","author":"X Gao","year":"2019","unstructured":"Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397\u2013401 (2019).","journal-title":"Nature"},{"key":"486_CR36","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1016\/j.cmet.2019.02.015","volume":"29","author":"MR Sullivan","year":"2019","unstructured":"Sullivan, M. R. et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 29, 1410\u20131421 (2019).","journal-title":"Cell Metab."},{"key":"486_CR37","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S0899-9007(02)00780-3","volume":"18","author":"LA Cynober","year":"2002","unstructured":"Cynober, L. A. Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18, 761\u2013766 (2002).","journal-title":"Nutrition"},{"key":"486_CR38","doi-asserted-by":"publisher","unstructured":"Ghergurovich, J. M. et al. Methionine synthase supports tumor tetrahydrofolate pools. Nat. Metab. https:\/\/doi.org\/10.1038\/s42255-021-00465-w (2021).","DOI":"10.1038\/s42255-021-00465-w"},{"key":"486_CR39","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0163-7258(96)00197-0","volume":"73","author":"JM Mato","year":"1997","unstructured":"Mato, J. M., Alvarez, L., Ortiz, P. & Pajares, M. A. S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol. Ther. 73, 265\u2013280 (1997).","journal-title":"Pharmacol. Ther."},{"key":"486_CR40","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.molcel.2015.12.014","volume":"61","author":"OD Maddocks","year":"2016","unstructured":"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, 210\u2013221 (2016).","journal-title":"Mol. Cell"},{"key":"486_CR41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cbpa.2015.10.030","volume":"30","author":"X Su","year":"2016","unstructured":"Su, X., Wellen, K. E. & Rabinowitz, J. D. Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30, 52\u201360 (2016).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"486_CR42","volume":"3","author":"HS Cho","year":"2012","unstructured":"Cho, H. S. et al. Enhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B. Nat. Commun. 3, 1072 (2012).","journal-title":"Nat. Commun."},{"key":"486_CR43","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1126\/science.aao3265","volume":"358","author":"X Gu","year":"2017","unstructured":"Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813\u2013818 (2017).","journal-title":"Science"},{"key":"486_CR44","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1093\/jn\/127.5.838S","volume":"127","author":"PG Reeves","year":"1997","unstructured":"Reeves, P. G. Components of the AIN-93 Diets as Improvements in the AIN-76A Diet. J. Nutr. 127, 838\u2013841 (1997).","journal-title":"J. Nutr."},{"key":"486_CR45","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3945\/ajcn.2009.28427","volume":"91","author":"L Bailey, R","year":"2010","unstructured":"Bailey, R, L. et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003\u20132006. Am. J. Clin. Nutr. 91, 231\u2013237 (2010).","journal-title":"Am. J. Clin. Nutr."},{"key":"486_CR46","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/bjc.1983.105","volume":"47","author":"J Gaukroger","year":"1983","unstructured":"Gaukroger, J. et al. Paradoxical response of malignant melanoma to methotrexate in vivo and in vitro. Br. J. Cancer 47, 671\u2013679 (1983).","journal-title":"Br. J. Cancer"},{"key":"486_CR47","doi-asserted-by":"crossref","first-page":"8470","DOI":"10.1016\/S0021-9258(19)38912-4","volume":"265","author":"E Chu","year":"1990","unstructured":"Chu, E., Drake, J. C., Boarman, D., Baram, J. & Allegra, C. J. Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells. J. Biol. Chem. 265, 8470\u20138478 (1990).","journal-title":"J. Biol. Chem."},{"key":"486_CR48","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41568-019-0187-8","volume":"19","author":"SM Sanderson","year":"2019","unstructured":"Sanderson, S. M., Gao, X., Dai, Z. & Locasale, J. W. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat. Rev. Cancer 19, 625\u2013637 (2019).","journal-title":"Nat. Rev. Cancer"},{"key":"486_CR49","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.bcp.2018.05.003","volume":"154","author":"S Chaturvedi","year":"2018","unstructured":"Chaturvedi, S., Hoffman, R. M. & Bertino, J. R. Exploiting methionine restriction for cancer treatment. Biochem. Pharmacol. 154, 170\u2013173 (2018).","journal-title":"Biochem. Pharmacol."},{"key":"486_CR50","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/leu.2017.283","volume":"32","author":"T Sakura","year":"2017","unstructured":"Sakura, T. et al. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia 32, 626\u2013632 (2017).","journal-title":"Leukemia"},{"key":"486_CR51","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.2165\/11202640-000000000-00000","volume":"69","author":"CM Baldwin","year":"2009","unstructured":"Baldwin, C. M. & Perry, C. M. Pemetrexed: a review in its use in the management of advanced non-squamous non-small cell lung cancer. Drugs 69, 2279\u20132302 (2009).","journal-title":"Drugs"},{"key":"486_CR52","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.drup.2012.07.002","volume":"15","author":"N Gonen","year":"2012","unstructured":"Gonen, N. & Assaraf, Y. G. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist. Updat. 15, 183\u2013210 (2012).","journal-title":"Drug Resist. Updat."},{"key":"486_CR53","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.hoc.2012.02.002","volume":"26","author":"M Visentin","year":"2012","unstructured":"Visentin, M., Zhao, R. & Goldman, I. D. The antifolates. Hematol. Oncol. Clin. North Am. 26, 629\u2013648 (2012).","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"486_CR54","first-page":"937","volume":"7","author":"X Li","year":"2014","unstructured":"Li, X., Wei, S. & Chen, J. Critical appraisal of pemetrexed in the treatment of NSCLC and metastatic pulmonary nodules. Onco. Targets Ther. 7, 937\u2013945 (2014).","journal-title":"Onco. Targets Ther."},{"key":"486_CR55","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1111\/j.1349-7006.1999.tb00704.x","volume":"90","author":"Y Otake","year":"1999","unstructured":"Otake, Y. et al. Expression of thymidylate synthase in human non-small cell lung cancer. Jpn. J. Cancer Res. 90, 1248\u20131253 (1999).","journal-title":"Jpn. J. Cancer Res."},{"key":"486_CR56","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/cncr.22208","volume":"107","author":"P Ceppi","year":"2006","unstructured":"Ceppi, P. et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107, 1589\u20131596 (2006).","journal-title":"Cancer"},{"key":"486_CR57","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1038\/bjc.2011.129","volume":"104","author":"K Takezawa","year":"2011","unstructured":"Takezawa, K. et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br. J. Cancer 104, 1594\u20131601 (2011).","journal-title":"Br. J. Cancer"},{"key":"486_CR58","volume":"8","author":"Y Li","year":"2018","unstructured":"Li, Y. et al. Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data. Sci. Rep. 8, 15834 (2018).","journal-title":"Sci. Rep."},{"key":"486_CR59","doi-asserted-by":"crossref","first-page":"13186","DOI":"10.1074\/jbc.R113.458810","volume":"288","author":"C Gherasim","year":"2013","unstructured":"Gherasim, C., Lofgren, M. & Banerjee, R. Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin. J. Biol. Chem. 288, 13186\u201313193 (2013).","journal-title":"J. Biol. Chem."},{"key":"486_CR60","doi-asserted-by":"crossref","first-page":"20778","DOI":"10.1074\/jbc.M300845200","volume":"278","author":"S Oltean","year":"2003","unstructured":"Oltean, S. & Banerjee, R. Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. J. Biol. Chem. 278, 20778\u201320784 (2003).","journal-title":"J. Biol. Chem."},{"key":"486_CR61","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0076-6879(97)81026-9","volume":"281","author":"JT Jarrett","year":"1997","unstructured":"Jarrett, J. T., Goulding, C. W., Fluhr, K., Huang, S. & Matthews, R. G. Purification and assay of cobalamin-dependent methionine synthase from Escherichia coli. Methods Enzymol. 281, 196\u2013213 (1997).","journal-title":"Methods Enzymol."},{"key":"486_CR62","doi-asserted-by":"crossref","first-page":"9476","DOI":"10.1073\/pnas.0603694103","volume":"103","author":"K Yamada","year":"2006","unstructured":"Yamada, K., Gravel, R. A., Toraya, T. & Matthews, R. G. Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Proc. Natl Acad. Sci. USA 103, 9476\u20139481 (2006).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"486_CR63","doi-asserted-by":"crossref","first-page":"35558","DOI":"10.1074\/jbc.M103707200","volume":"276","author":"H Olteanu","year":"2001","unstructured":"Olteanu, H. & Banerjee, R. Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. J. Biol. Chem. 276, 35558\u201335563 (2001).","journal-title":"J. Biol. Chem."},{"key":"486_CR64","doi-asserted-by":"publisher","unstructured":"Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife https:\/\/doi.org\/10.7554\/eLife.27713 (2017).","DOI":"10.7554\/eLife.27713"},{"key":"486_CR65","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.cell.2015.07.017","volume":"162","author":"LB Sullivan","year":"2015","unstructured":"Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552\u2013563 (2015).","journal-title":"Cell"},{"key":"486_CR66","doi-asserted-by":"crossref","first-page":"4444","DOI":"10.1039\/c3cc41437j","volume":"49","author":"H Zhao","year":"2013","unstructured":"Zhao, H., French, J. B., Fang, Y. & Benkovic, S. J. The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans. Chem. Commun. 49, 4444\u20134452 (2013).","journal-title":"Chem. Commun."},{"key":"486_CR67","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.copbio.2017.03.010","volume":"48","author":"A Okesli","year":"2017","unstructured":"Okesli, A., Khosla, C. & Bassik, M. C. Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy. Curr. Opin. Biotechnol. 48, 127\u2013134 (2017).","journal-title":"Curr. Opin. Biotechnol."},{"key":"486_CR68","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nmeth.3047","volume":"11","author":"NE Sanjana","year":"2014","unstructured":"Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783\u2013784 (2014).","journal-title":"Nat. Methods"},{"key":"486_CR69","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.cell.2015.11.015","volume":"163","author":"T Hart","year":"2015","unstructured":"Hart, T. et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163, 1515\u20131526 (2015).","journal-title":"Cell"},{"key":"486_CR70","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/s41586-018-0316-7","volume":"559","author":"N Kanarek","year":"2018","unstructured":"Kanarek, N. et al. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 559, 632\u2013636 (2018).","journal-title":"Nature"},{"key":"486_CR71","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/s41586-020-2969-2","volume":"588","author":"X Jin","year":"2020","unstructured":"Jin, X. et al. A metastasis map of human cancer cell lines. Nature 588, 331\u2013336 (2020).","journal-title":"Nature"}],"container-title":["Nature Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42255-021-00486-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42255-021-00486-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42255-021-00486-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T15:38:20Z","timestamp":1670081900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42255-021-00486-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":71,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["486"],"URL":"https:\/\/doi.org\/10.1038\/s42255-021-00486-5","relation":{},"ISSN":["2522-5812"],"issn-type":[{"value":"2522-5812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"assertion":[{"value":"13 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.G.V.H. is on the scientific advisory board of Agios Pharmaceuticals, Aeglea Biotherapeutics, iTeos Therapeutics, Faeth Therapeutics, Sage Therapeutics, DRIOA Ventures and Auron Therapeutics. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}