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Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential

Abstract

Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.

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Fig. 1: Compartmentalization of the mammalian one-carbon metabolism to mitochondria and cytosol.
Fig. 2: Chemical structure of folate.
Fig. 3: Reaction scheme of key enzymes in the 1C pathway.
Fig. 4: Our computational model of MTHFD2·NAD+·Pi·Mg2+·Pi·THF system.
Fig. 5: Our computational model of MTHFD2·NAD+·P ·THF system without Mg+.

References

  1. 1.

    Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10:671–84.

    Google Scholar 

  3. 3.

    McGuirk S, Audet-Delage Y, St-Pierre J. Metabolic fitness and plasticity in cancer progression. Trends Cancer. 2020;6:49–61.

    CAS  PubMed  Google Scholar 

  4. 4.

    Kreuzaler P, Panina Y, Segal J, Yuneva M. Adapt and conquer: metabolic flexibility in cancer growth, invasion and evasion. Mol Metab. 2020;33:83–101.

    CAS  PubMed  Google Scholar 

  5. 5.

    Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;39:191–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Choi Y-K, Park K-G. Targeting glutamine metabolism for cancer treatment. Biomol Ther. 2018;26:19–28.

    CAS  Google Scholar 

  8. 8.

    Fadaka A, Ajiboye B, Ojo O, Adewale O, Olayide I, Emuowhochere R. Biology of glucose metabolization in cancer cells. J Oncological Sci. 2017;3:45–51.

    Google Scholar 

  9. 9.

    Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9:18699.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Lin J, Xia L, Liang J, Han Y, Wang H, Oyang L, et al. The roles of glucose metabolic reprogramming in chemo- and radio-resistance. J Exp Clin Cancer Res. 2019;38:218.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948;238:787–93.

    CAS  PubMed  Google Scholar 

  12. 12.

    Chattopadhyay S, Moran RG, Goldman ID. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther. 2007;6:404–17.

    CAS  PubMed  Google Scholar 

  13. 13.

    Estrada A, Wright DL, Anderson AC. Antibacterial antifolates: from development through resistance to the next generation. Cold Spring Harb Perspect Med. 2016;6. https://doi.org/10.1101/cshperspect.a028324.

  14. 14.

    Purcell WT, Ettinger DS. Novel antifolate drugs. Curr Oncol Rep. 2003;5:114–25.

    PubMed  Google Scholar 

  15. 15.

    Carver JR, Szalda D, Ky B. Asymptomatic cardiac toxicity in long-term cancer survivors: defining the population and recommendations for surveillance. Semin Oncol. 2013;40:229–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Yeh Edward TH, Tong Ann T, Lenihan Daniel J, Wamique YusufS, Joseph Swafford, Christopher Champion, et al. Cardiovascular complications of cancer therapy. Circulation. 2004;109:3122–31.

    CAS  PubMed  Google Scholar 

  17. 17.

    Wang Y, Probin V, Zhou D. Cancer therapy-induced residual bone marrow injury-mechanisms of induction and implication for therapy. Curr Cancer Ther Rev. 2006;2:271–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Appling DR. Compartmentation of folate-mediated one-carbon metabolism in eukaryotes. FASEB J.1991;5(12):2645–51.

    CAS  PubMed  Google Scholar 

  19. 19.

    Toriello HV. Folic acid and neural tube defects. Genet Med. 2005;7:283–4.

    PubMed  Google Scholar 

  20. 20.

    Kujovich JL. Evaluation of anemia. Obstet Gynecol Clin North Am. 2016;43:247–64.

    PubMed  Google Scholar 

  21. 21.

    Fox JT, Stover PJ. Folate-mediated one-carbon metabolism. Vitam Horm. 2008;79:1–44.

    CAS  PubMed  Google Scholar 

  22. 22.

    Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27–42.

    CAS  PubMed  Google Scholar 

  23. 23.

    Agapakis CM, Boyle PM, Silver PA. Natural strategies for the spatial optimization of metabolism in synthetic biology. Nat Chem Biol. 2012;8:527–35.

    CAS  PubMed  Google Scholar 

  24. 24.

    Kit S. The biosynthesis of free glycine and serine by tumors. Cancer Res. 1955;15:715–8.

    CAS  PubMed  Google Scholar 

  25. 25.

    Labuschagne CF, van den Broek NJF, Mackay GM, Vousden KH, Maddocks ODK. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 2014;7:1248–58.

    CAS  PubMed  Google Scholar 

  26. 26.

    Shin M, Bryant JD, Momb J, Appling DR. Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues. J Biol Chem. 2014;289:15507–17.

    CAS  PubMed  Google Scholar 

  27. 27.

    Cybulski RL, Fisher RR. Intramitochondrial localization and proposed metabolic significance of serine transhydroxymethylase. Biochemistry. 1976;15:3183–7.

    CAS  PubMed  Google Scholar 

  28. 28.

    Balut C, vandeVen M, Despa S, Lambrichts I, Ameloot M, Steels P, et al. Measurement of cytosolic and mitochondrial pH in living cells during reversible metabolic inhibition. Kidney Int. 2008;73:226–32.

    CAS  PubMed  Google Scholar 

  29. 29.

    Boron WF. Regulation of intracellular pH. Adv Physiol Educ. 2004;28:160–79.

    PubMed  Google Scholar 

  30. 30.

    Shirmanova MV, Druzhkova IN, Lukina MM, Matlashov ME, Belousov VV, Snopova LB, et al. Intracellular pH imaging in cancer cells in vitro and tumors in vivo using the new genetically encoded sensor SypHer2. Biochim Biophys Acta (BBA) - Gen Subj. 2015;1850:1905–11.

    CAS  Google Scholar 

  31. 31.

    White KA, Grillo-Hill BK, Barber DL. Cancer cell behaviors mediated by dysregulated pH dynamics at a glance. J Cell Sci. 2017;130:663–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hu Y, Li Y. Effect of low pH treatment on cell cycle and cell growth. FASEB J. 2018;32:804.49.

    Google Scholar 

  33. 33.

    Vazquez A, Tedeschi PM, Bertino JR. Overexpression of the mitochondrial folate and glycine–serine pathway: a new determinant of methotrexate selectivity in tumors. Cancer Res. 2013;73:478–82.

    CAS  PubMed  Google Scholar 

  34. 34.

    Noguchi K, Konno M, Koseki J, Nishida N, Kawamoto K, Yamada D, et al. The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer. Oncol Lett. 2018;16:1827–34.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014;5:3128.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Agarwal S, Behring M, Hale K, Al Diffalha S, Wang K, Manne U, et al. MTHFD1L, a folate cycle enzyme, is involved in progression of colorectal cancer. Transl Oncol. 2019;12:1461–7.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Eich M-L, Rodriguez Pena MDC, Chandrashekar DS, Chaux A, Agarwal S, Gordetsky JB, et al. Expression and role of methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) in bladder cancer. Transl Oncol. 2019;12:1416–24.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Lee D, Xu IM-J, Chiu DK-C, Lai RK-H, Tse AP-W, Lan Li L, et al. Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Investig. 2017;127:1856–72.

    PubMed  Google Scholar 

  39. 39.

    Wu M, Wanggou S, Li X, Liu Q, Xie Y. Overexpression of mitochondrial serine hydroxyl-methyltransferase 2 is associated with poor prognosis and promotes cell proliferation and invasion in gliomas. Onco Targets Ther. 2017;10:3781–8.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Tedeschi PM, Vazquez A, Kerrigan JE, Bertino JR. Mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) overexpression is associated with tumor cell proliferation and is a novel target for drug development. Mol Cancer Res. 2015;13:1361–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Liu Y, Yin C, Deng M-M, Wang Q, He X-Q, Li M-T, et al. High expression of SHMT2 is correlated with tumor progression and predicts poor prognosis in gastrointestinal tumors. Eur Rev Med Pharm Sci. 2019;23:9379–92.

    CAS  Google Scholar 

  42. 42.

    Di Pietro E, Sirois J, Tremblay ML, MacKenzie RE. Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is essential for embryonic development. Mol Cell Biol. 2002;22:4158–66.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Stover PJ, Chen LH, Suh JR, Stover DM, Keyomarsi K, Shane B. Molecular cloning, characterization, and regulation of the human mitochondrial serine hydroxymethyltransferase gene. J Biol Chem. 1997;272:1842–8.

    CAS  PubMed  Google Scholar 

  44. 44.

    Florio R, di Salvo ML, Vivoli M, Contestabile R. Serine hydroxymethyltransferase: a model enzyme for mechanistic, structural, and evolutionary studies. Biochim Biophys Acta. 2011;1814:1489–96.

    CAS  PubMed  Google Scholar 

  45. 45.

    Giardina G, Brunotti P, Fiascarelli A, Cicalini A, Costa MGS, Buckle AM, et al. How pyridoxal 5′-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state. FEBS J. 2015;282:1225–41.

    CAS  PubMed  Google Scholar 

  46. 46.

    Yang X, Wang Z, Li X, Liu B, Liu M, Liu L, et al. SHMT2 Desuccinylation by SIRT5 drives cancer cell proliferation. Cancer Res. 2018;78:372–86.

    PubMed  Google Scholar 

  47. 47.

    Morscher RJ, Ducker GS, Li SH-J, Mayer JA, Gitai Z, Sperl W, et al. Mitochondrial translation requires folate-dependent tRNA methylation. Nature. 2018;554:128–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Lucas S, Chen G, Aras S, Wang J. Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells. Life Sci Alliance. 2018;1:e201800036.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Anderson DD, Stover PJ. SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS ONE. 2009;4:e5839.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Guiducci G, Paone A, Tramonti A, Giardina G, Rinaldo S, Bouzidi A, et al. The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism. Nucleic Acids Res. 2019;47:4240–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Anderson DD, Eom JY, Stover PJ. Competition between sumoylation and ubiquitination of serine hydroxymethyltransferase 1 determines its nuclear localization and its accumulation in the nucleus. J Biol Chem. 2012;287:4790–9.

    CAS  PubMed  Google Scholar 

  52. 52.

    Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012;336:1040–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lee GY, Haverty PM, Li L, Kljavin NM, Bourgon R, Lee J, et al. Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer Res. 2014;74:3114–26.

    CAS  PubMed  Google Scholar 

  54. 54.

    Tani H, Ohnishi S, Shitara H, Mito T, Yamaguchi M, Yonekawa H, et al. Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal. Sci Rep. 2018;8:425.

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Minton DR, Nam M, McLaughlin DJ, Shin J, Bayraktar EC, Alvarez SW, et al. Serine catabolism by SHMT2 is required for proper mitochondrial translation initiation and maintenance of formylmethionyl-tRNAs. Mol Cell. 2018;69:610–21.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ning S, Ma S, Saleh AQ, Guo L, Zhao Z, Chen Y. SHMT2 overexpression predicts poor prognosis in intrahepatic cholangiocarcinoma. Gastroenterol Res Pract. 2018;2018:4369253.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Wang H, Chong T, Li B-Y, Chen X-S, Zhen W-B. Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer. Biol Res. 2020;53:46.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Woo CC, Chen WC, Teo XQ, Radda GK, Teck Hock Lee P. Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget. 2016;7:53005–17.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Nonaka H, Nakanishi Y, Kuno S, Ota T, Mochidome K, Saito Y, et al. Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction. Nat Commun. 2019;10:876.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Snell K, Riches D. Effects of a triazine antifolate (NSC 127755) on serine hydroxymethyltransferase in myeloma cells in culture. Cancer Lett. 1989;44:217–20.

    CAS  PubMed  Google Scholar 

  61. 61.

    Stover P, Schirch V. 5-Formyltetrahydrofolate polyglutamates are slow tight binding inhibitors of serine hydroxymethyltransferase. J Biol Chem. 1991;266:1543–50.

    CAS  PubMed  Google Scholar 

  62. 62.

    Marani M, Paone A, Fiascarelli A, Macone A, Gargano M, Rinaldo S, et al. A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells. Oncotarget. 2016;7:4570–83.

    PubMed  Google Scholar 

  63. 63.

    Gu Y, Si J, Xiao X, Tian Y, Yang S. miR-92a inhibits proliferation and induces apoptosis by regulating methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression in acute myeloid leukemia. Oncol Res. 2017;25:1069–79.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Koseki J, Konno M, Asai A, Colvin H, Kawamoto K, Nishida N, et al. Enzymes of the one-carbon folate metabolism as anticancer targets predicted by survival rate analysis. Sci Rep. 2018;8:303.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Yan Y, Zhang D, Lei T, Zhao C, Han J, Cui J, et al. MicroRNA-33a-5p suppresses colorectal cancer cell growth by inhibiting MTHFD2. Clin Exp Pharm Physiol. 2019;46:928–36.

    CAS  Google Scholar 

  66. 66.

    Ju H-Q, Lu Y-X, Chen D-L, Zuo Z-X, Liu Z-X, Wu Q-N, et al. Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: mechanisms and therapeutic implications. J Natl Cancer Inst. 2018. https://doi.org/10.1093/jnci/djy160.

  67. 67.

    Xu T, Zhang K, Shi J, Huang B, Wang X, Qian K, et al. MicroRNA-940 inhibits glioma progression by blocking mitochondrial folate metabolism through targeting of MTHFD2. Am J Cancer Res. 2019;9:250–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Nishimura T, Nakata A, Chen X, Nishi K, Meguro-Horike M, Sasaki S, et al. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. Oncogene. 2019;38:2464–81.

    CAS  PubMed  Google Scholar 

  69. 69.

    Lin H, Huang B, Wang H, Liu X, Hong Y, Qiu S, et al. MTHFD2 overexpression predicts poor prognosis in renal cell carcinoma and is associated with cell proliferation and vimentin-modulated migration and invasion. Cell Physiol Biochem. 2018;51:991–1000.

    CAS  PubMed  Google Scholar 

  70. 70.

    Asai A, Koseki J, Konno M, Nishimura T, Gotoh N, Satoh T, et al. Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2. Heliyon. 2018;4:e01021.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Mejia NR, MacKenzie RE. NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells. J Biol Chem. 1985;260:14616–20.

    CAS  PubMed  Google Scholar 

  72. 72.

    Mejia NR, MacKenzie RE. NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase in transformed cells is a mitochondrial enzyme. Biochem Biophys Res Commun. 1988;155:1–6.

    CAS  PubMed  Google Scholar 

  73. 73.

    Patel H, Pietro ED, MacKenzie RE. Mammalian fibroblasts lacking mitochondrial NAD+-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase are glycine auxotrophs. J Biol Chem. 2003;278:19436–41.

    CAS  PubMed  Google Scholar 

  74. 74.

    Yu C, Yang L, Cai M, Zhou F, Xiao S, Li Y, et al. Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes. J Cell Mol Med. 2020;24:1568–77.

    CAS  PubMed  Google Scholar 

  75. 75.

    Gustafsson R, Jemth A-S, Gustafsson NMS, Färnegårdh K, Loseva O, Wiita E, et al. Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitor. Cancer Res. 2017;77:937–48.

    CAS  PubMed  Google Scholar 

  76. 76.

    Fu C, Sikandar A, Donner J, Zaburannyi N, Herrmann J, Reck M, et al. The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. Nat Commun. 2017;8:1529.

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kawai J, Ota M, Ohki H, Toki T, Suzuki M, Shimada T, et al. Structure-based design and synthesis of an isozyme-selective MTHFD2 inhibitor with a tricyclic coumarin scaffold. ACS Med Chem Lett. 2019;10:893–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Kawai J, Toki T, Ota M, Inoue H, Takata Y, Asahi T, et al. Discovery of a potent, selective, and orally available MTHFD2 inhibitor (DS18561882) with in vivo antitumor activity. J Med Chem. 2019. https://doi.org/10.1021/acs.jmedchem.9b01113.

  79. 79.

    Rios-Orlandi EM, MacKenzie RE. The activities of the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase from ascites tumor cells are kinetically independent. J Biol Chem. 1988;263:4662–7.

    CAS  PubMed  Google Scholar 

  80. 80.

    Shin M, Momb J, Appling DR. Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase. Cancer Metab. 2017;5:11.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Gustafsson Sheppard N, Jarl L, Mahadessian D, Strittmatter L, Schmidt A, Madhusudan N, et al. The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation. Sci Rep. 2015;5:15029.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Koufaris C, Nilsson R. Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation. Cancer Metab. 2018;6:12.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Kg P, Re M. NAD+-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase: detection of the mRNA in normal murine tissues and transcriptional regulation of the gene in cell lines. Biochim Biophys Acta. 1993;1171:281–7.

    Google Scholar 

  84. 84.

    Bolusani S, Young BA, Cole NA, Tibbetts AS, Momb J, Bryant JD, et al. Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues. J Biol Chem. 2011;286:5166–74.

    CAS  PubMed  Google Scholar 

  85. 85.

    Nilsson R, Nicolaidou V, Koufaris C. Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer. Gene. 2019;716:144032.

    CAS  PubMed  Google Scholar 

  86. 86.

    Prasannan P, Pike S, Peng K, Shane B, Appling DR. Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. J Biol Chem. 2003;278:43178–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Momb J, Lewandowski JP, Bryant JD, Fitch R, Surman DR, Vokes SA, et al. Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice. PNAS. 2013;110:549–54.

    CAS  PubMed  Google Scholar 

  88. 88.

    Krupenko NI, Dubard ME, Strickland KC, Moxley KM, Oleinik NV, Krupenko SA. ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2010;285:23056–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Sarret C, Ashkavand Z, Paules E, Dorboz I, Pediaditakis P, Sumner S, et al. Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome. NPJ Genom Med. 2019;4:17.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Schober AF, Mathis AD, Ingle C, Park JO, Chen L, Rabinowitz JD, et al. A two-enzyme adaptive unit within bacterial folate metabolism. Cell Rep. 2019;27:3359–70.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. PNAS. 2011;108:15163–8.

    CAS  PubMed  Google Scholar 

  92. 92.

    Organista-Nava J, Gómez-Gómez Y, Illades-Aguiar B, Rivera-Ramírez AB, Saavedra-Herrera MV, Leyva-Vázquez MA. Overexpression of dihydrofolate reductase is a factor of poor survival in acute lymphoblastic leukemia. Oncol Lett. 2018;15:8405–11.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Raimondi MV, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D, et al. DHFR inhibitors: reading the past for discovering novel anticancer agents. Molecules. 2019;24:1140.

    PubMed Central  Google Scholar 

  94. 94.

    Raimondi MV, Randazzo O, La Franca M, Barone G, Vignoni E, Rossi D. et al. DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents. Molecules. 2019;24:1140

    PubMed Central  Google Scholar 

  95. 95.

    Schweitzer BI, Dicker AP, Bertino JR. Dihydrofolate reductase as a therapeutic target. The FASEB J. 1990;4:2441–52.

    CAS  PubMed  Google Scholar 

  96. 96.

    Patel SN, Kain KC. Atovaquone/proguanil for the prophylaxis and treatment of malaria. Expert Rev Anti Infect Ther. 2005;3:849–61.

    CAS  PubMed  Google Scholar 

  97. 97.

    Wróbel A, Arciszewska K, Maliszewski D, Drozdowska D. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. J Antibiotics. 2020;73:5–27.

    Google Scholar 

  98. 98.

    Srinivasan B, Skolnick J. Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors. FEBS J. 2015;282:1922–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Rajagopalan PTR, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG. Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics. Proc Natl Acad Sci USA. 2002;99:13481–6.

    CAS  PubMed  Google Scholar 

  100. 100.

    Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum. 2004;50:1370–82.

    CAS  PubMed  Google Scholar 

  101. 101.

    Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, et al. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. PNAS. 2012;109:16823–8.

    CAS  PubMed  Google Scholar 

  102. 102.

    Agarwal PK, Billeter SR, Rajagopalan PTR, Benkovic SJ, Hammes-Schiffer S. Network of coupled promoting motions in enzyme catalysis. PNAS. 2002;99:2794–9.

    CAS  PubMed  Google Scholar 

  103. 103.

    Cario H, Smith DEC, Blom H, Blau N, Bode H, Holzmann K, et al. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011;88:226–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Kotoula V, Krikelis D, Karavasilis V, Koletsa T, Eleftheraki AG, Televantou D, et al. Expression of DNA repair and replication genes in non-small cell lung cancer (NSCLC): a role for thymidylate synthetase (TYMS). BMC Cancer. 2012;12:342.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Burdelski C, Strauss C, Tsourlakis MC, Kluth M, Hube-Magg C, Melling N, et al. Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer. Oncotarget. 2015;6:8377–87.

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Calvert AH, Alison DL, Harland SJ, Robinson BA, Jackman AL, Jones TR, et al. A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol. 1986;4:1245–52.

    CAS  PubMed  Google Scholar 

  107. 107.

    Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, et al. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharm. 1996;37:509–17.

    CAS  Google Scholar 

  108. 108.

    Duch DS, Banks S, Dev IK, Dickerson SH, Ferone R, Heath LS, et al. Biochemical and cellular pharmacology of 1843U89, a novel benzoquinazoline inhibitor of thymidylate synthase. Cancer Res. 1993;53:810–8.

    CAS  PubMed  Google Scholar 

  109. 109.

    Chu E, Callender MA, Farrell MP, Schmitz JC. Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharm. 2003;52:80–9.

    Google Scholar 

  110. 110.

    Peters GJ, Backus HHJ, Freemantle S, van Triest B, Codacci-Pisanelli G, van der Wilt CL, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta. 2002;1587:194–205.

    CAS  PubMed  Google Scholar 

  111. 111.

    Chen D, Jansson A, Sim D, Larsson A, Nordlund P. Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states. J Biol Chem. 2017;292:13449–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Lovelace LL, Johnson SR, Gibson LM, Bell BJ, Berger SH, Lebioda L. Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation. Protein Sci. 2009;18:1628–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Huang X, Gibson LM, Bell BJ, Lovelace LL, Peña MMO, Berger FG, et al. Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability. Biochemistry. 2010;49:2475–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Peters EJ, Kraja AT, Lin SJ, Yen-Revollo JL, Marsh S, Province MA, et al. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity. Pharmacogenet Genom. 2009;19:399–401.

    CAS  Google Scholar 

  115. 115.

    Brodsky G, Barnes T, Bleskan J, Becker L, Cox M, Patterson D. The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with Down syndrome. Hum Mol Genet. 1997;6:2043–50.

    CAS  PubMed  Google Scholar 

  116. 116.

    Deis SM, Doshi A, Hou Z, Matherly LH, Gangjee A, Dann CE. Structural and enzymatic analysis of tumor-targeted antifolates that inhibit glycinamide ribonucleotide formyltransferase. Biochemistry. 2016;55:4574–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Bronder JL, Moran RG. Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function. Cancer Res. 2002;62:5236–41.

    CAS  PubMed  Google Scholar 

  118. 118.

    Robert F, Garrett C, Dinwoodie WR, Sullivan DM, Bishop M, Amantea M, et al. Results of 2 phase I studies of intravenous (iv) pelitrexol (AG2037), a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, in patients (pts) with solid tumors. J Clin Onocol. 2004;22:3075.

    Google Scholar 

  119. 119.

    Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL. et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997;57:1116–23.

    CAS  PubMed  Google Scholar 

  120. 120.

    Welin M, Grossmann JG, Flodin S, Nyman T, Stenmark P, Trésaugues L, et al. Structural studies of tri-functional human GART. Nucleic Acids Res. 2010;38:7308–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Burda P, Kuster A, Hjalmarson O, Suormala T, Bürer C, Lutz S, et al. Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment. J Inherit Metab Dis. 2015;38:863–72.

    CAS  PubMed  Google Scholar 

  122. 122.

    Sdelci S, Rendeiro AF, Rathert P, You W, Lin J-MG, Ringler A, et al. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat Genet. 2019;51:990–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    New Antifolates in Clinical Development. Cancer Network. https://www.cancernetwork.com/view/new-antifolates-clinical-development.

  124. 124.

    Pikman Y, Puissant A, Alexe G, Furman A, Chen LM, Frumm SM, et al. Targeting MTHFD2 in acute myeloid leukemia. J Exp Med. 2016;213:1285–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Zeller KI, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 2003;4:R69.

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Vazquez A, Markert EK, Oltvai ZN. Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS ONE. 2011;6:e25881.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer. 2017;17:502–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Sneader W. Drug discovery: a history. UK: John Wiley & Sons; 2005. https://books.google.se/books?id=jglFsz5EJR8C&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false.

  129. 129.

    Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem. 2018;158:502–16.

    CAS  PubMed  Google Scholar 

  130. 130.

    Zachariae H. Methotrexate side-effects. Br J Dermatol. 1990;122:127–33.

    PubMed  Google Scholar 

  131. 131.

    Albrecht K, Müller-Ladner U. Side effects and management of side effects of methotrexate in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S95–101.

    CAS  PubMed  Google Scholar 

  132. 132.

    Chan ESL, Cronstein BN. Methotrexate—how does it really work? Nat Rev Rheumatol. 2010;6:175–8.

    CAS  PubMed  Google Scholar 

  133. 133.

    Bertino JR, Göker E, Gorlick R, Li WW, Banerjee D. Resistance mechanisms to methotrexate in tumors. Stem Cells. 1996;14:5–9.

    CAS  PubMed  Google Scholar 

  134. 134.

    Nagura E. [Methotrexate and its drug resistance]. Gan Kagaku Ryoho. 1988;15:2882–7.

    CAS  Google Scholar 

  135. 135.

    Wang J, Li G. Mechanisms of methotrexate resistance in osteosarcoma cell lines and strategies for overcoming this resistance. Oncol Lett. 2015;9:940–4.

    PubMed  Google Scholar 

  136. 136.

    Wojtuszkiewicz A, Peters GJ, van Woerden NL, Dubbelman B, Escherich G, Schmiegelow K, et al. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. J Hematol Oncol. 2015;8:61.

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Frantz M-C, Wipf P. Mitochondria as a target in treatment. Environ Mol Mutagen. 2010;51:462–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Medwig-Kinney TN, Smith JJ, Palmisano NJ, Tank S, Zhang W, Matus DQ. A developmental gene regulatory network for C. elegans anchor cell invasion. Development. 2020;147. https://doi.org/10.1242/dev.185850.

  139. 139.

    Ducker GS, Chen L, Morscher RJ, Ghergurovich JM, Esposito M, Teng X, et al. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 2016;23:1140–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Toyama BH, Hetzer MW. Protein homeostasis: live long, won’t prosper. Nat Rev Mol Cell Biol. 2013;14:55–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. From RNA to protein. In: Molecular biology of the cell. 4th ed. New York: Garland Science; 2002. https://www.ncbi.nlm.nih.gov/books/NBK26829/.

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Acknowledgements

LNZ was supported by an A*STAR International Fellowship (AIF) from Singapore. This work is supported by the IngaBritt och Arne Lundbergs Forskningsstiftelse LU2020-0013; PK is supported by the Faculty of Medicine, Lund University; the Swedish Foundation for Strategic Research Dnr IRC15-0067, and Swedish Research Council, Strategic Research Area EXODIAB, Dnr 2009–1039. LNZ would like to thank Prof. Chew Lock Yue (NTU) and Prof. Ulf Ryde (LU) for comments on the manuscript.

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Zhao, L.N., Björklund, M., Caldez, M.J. et al. Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential. Oncogene 40, 2339–2354 (2021). https://doi.org/10.1038/s41388-021-01695-8

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