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The role of methionine on metabolism, oxidative stress, and diseases


Methionine is an aliphatic, sulfur-containing, essential amino acid, and a precursor of succinyl-CoA, homocysteine, cysteine, creatine, and carnitine. Recent research has demonstrated that methionine can regulate metabolic processes, the innate immune system, and digestive functioning in mammals. It also intervenes in lipid metabolism, activation of endogenous antioxidant enzymes such as methionine sulfoxide reductase A, and the biosynthesis of glutathione to counteract oxidative stress. In addition, methionine restriction prevents altered methionine/transmethylation metabolism, thereby decreasing DNA damage and carcinogenic processes and possibly preventing arterial, neuropsychiatric, and neurodegenerative diseases. This review focuses on the role of methionine in metabolism, oxidative stress, and related diseases.

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  1. Albers E (2009) Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5′-methylthioadenosine. IUBMB Life 61(12):1132–1142. doi:10.1002/iub.278

  2. Bauchart-Thevret C, Stoll B, Chacko S, Burrin DG (2009) Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs. Am J Physiol Endocrinol Metab 296(6):1239–1250. doi:10.1152/ajpendo.91021.2008

  3. Ben-Shachar D, Laifenfeld D (2004) Mitochondria, synaptic plasticity, and schizophrenia. Int Rev Neurobiol 59:273–296. doi:10.1016/S0074-7742(04)59011-6

  4. Blachier F, Mariotti F, Huneau JF, Tome D (2007) Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences. Amino Acids 33(4):547–562. doi:10.1007/s00726-006-0477-9

  5. Blachier F, Wu G, Yin Y (2013) Nutritional and physiological functions of amino acids in pigs. Springer, Vienna

  6. Campbell K, Vowinckel J, Keller MA, Ralser M (2016) Methionine metabolism alters oxidative stress resistance via the pentose phosphate pathway. Antioxid Redox Sign 24(10):543–547. doi:10.1089/ars.2015.6516

  7. Carew LB, McMurtry JP, Alster FA (2003) Effects of methionine deficiencies on plasma levels of thyroid hormones, insulin-like growth factors-I and -II, liver and body weights, and feed intake in growing chickens. Poult Sci 82(12):1932–1938. doi:10.1093/ps/82.12.1932

  8. Cassano T, Serviddio G, Gaetani S, Romano A, Dipasquale P, Cianci S, Bellanti F, Laconca L, Romano AD, Padalino I (2012) Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease. Neurobiol Aging 33(6):1121.e1121. doi:10.1016/j.neurobiolaging.2011.09.021

  9. Chen L, Yin YL, Jobgen WS, Jobgen SC, Knabe DA, Hu WX, Wu G (2007) In vitro oxidation of essential amino acids by jejunal mucosal cells of growing pigs. Livest Sci 109(1–3):19–23. doi:10.1016/j.livsci.2007.01.027

  10. Clay H, Sillivan S, Konradi C (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 29(3):311–324. doi:10.1016/j.ijdevneu.2010.08.007

  11. Costa MZ, Silva TMD, Flores NP, Schmitz F, Scherer EBDS, Viau CM, Saffi J, Barschak AG, Wyse ATDS, Spanevello RM (2013) Methionine and methionine sulfoxide alter parameters of oxidative stress in the liver of young rats: in vitro and in vivo studies. Mol Cell Biochem 384(1):21–28. doi:10.1007/s11010-013-1777-5

  12. D’Mello JPF, D’Mello J (2003) An outline of pathways in amino acid metabolism. In: D’Mello (ed) Amino acids in animal nutrition. CABI Publishing, Wallingford, pp 71–86

  13. Dash PK, Hergenroeder GW, Jeter CB, Choi HA, Kobori N, Moore AN (2016) Traumatic brain injury alters methionine metabolism: implications for pathophysiology. Front Syst Neurosci 10:36. doi:10.3389/fnsys.2016.00036

  14. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909

  15. Del BC, Martini D, Porrini M, Klimiszacas D, Riso P (2015) Berries and oxidative stress markers: an overview of human intervention studies. Food Funct 6(9):2890–2917. doi:10.1039/c5fo00657k

  16. Deng D, Yao K, Chu W, Li T, Huang R, Yin Y, Liu Z, Zhang J, Wu G (2009) Impaired translation initiation activation and reduced protein synthesis in weaned piglets fed a low-protein diet. J Nutr Biochem 20(7):544–552. doi:10.1016/j.jnutbio.2008.05.014

  17. Fang Z, Yao K, Zhang X, Zhao S, Sun Z, Tian G, Yu B, Lin Y, Zhu B, Jia G (2010) Nutrition and health relevant regulation of intestinal sulfur amino acid metabolism. Amino Acids 39(3):633–640. doi:10.1007/s00726-010-0502-x

  18. Finkelstein JD, Martin JJ, Harris BJ (1988) Methionine metabolism in mammals. The methionine-sparing effect of cystine. J Biol Chem 263(24):11750–11754

  19. Freitas I, Boncompagni E, Tarantola E, Gruppi C, Bertone V, Ferrigno A, Milanesi G, Vaccarone R, Tira ME, Vairetti M (2016) In situ evaluation of oxidative stress in rat fatty liver induced by a methionine- and choline-deficient diet. Oxid Med Cell Longev 201(2016):9307064. doi:10.1155/2016/9307064

  20. Garg SK, Yan Z, Vitvitsky V, Banerjee R (2011) Differential dependence on cysteine from transsulfuration versus transport during T cell activation. Antioxid Redox Sign 15(1):39–47. doi:10.1089/ars.2010.3496

  21. Gonsette RE (2008) Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J Neurol Sci 274(1–2):48–53. doi:10.1016/j.jns.2008.06.029

  22. He Q, Yin Y, Zhao F, Kong X, Wu G, Ren P (2011) Metabonomics and its role in amino acid nutrition research. Front Biosci Landmark 16(26):2451–2460

  23. Hidiroglou N, Gilani GS, Long L, Zhao X, Madere R, Cockell K, Belonge B, Ratnayake WMN, Peace R (2004) The influence of dietary vitamin E, fat, and methionine on blood cholesterol profile, homocysteine levels, and oxidizability of low density lipoprotein in the gerbil. J Nutr Biochem 15(12):730–740. doi:10.1016/j.jnutbio.2004.04.009

  24. Ho A, Michelson D, Aaen G, Ashwal S (2010) Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. J Child Neurol 25(7):898–900. doi:10.1177/0883073809343475

  25. Hoffman RM (1985) Altered methionine metabolism and transmethylation in cancer. Anticancer Res 5(1):1–30

  26. Hosseini SA, Zaghari M, Lotfollahian H, Shivazad M, Moravaj H (2012) Reevaluation of methionine requirement based on performance and immune responses in broiler breeder hens. J Poult Sci 49(1):26–33. doi:10.2141/jpsa.011021

  27. Hyelin H, Hyejun S, Feitelson MA, Yu DY (2010) Oxidative stress and antioxidants in hepatic pathogenesis. World J Gastroenterol 16(48):6035–6043

  28. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078. doi:10.1038/nature08467

  29. Kasahara A, Scorrano L (2014) Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol 24(12):761–770. doi:10.1016/j.tcb.2014.08.005

  30. Kim SW, Mateo RD, Yin YL, Wu G (2007) Functional amino acids and fatty acids for enhancing production performance of sows and piglets. Asian Austral J Anim 20(2):295–306. doi:10.5713/ajas.2007.295

  31. Kumagai H, Katoh S, Hirosawa K, Kimura M, Hishida A, Ikegaya N (2002) Renal tubulointerstitial injury in weanling rats with hyperhomocysteinemia. Kidney Int 62(4):1219–1228. doi:10.1111/j.1523-1755.2002.kid558.x

  32. Li T, Yin Y, Huang R, Zhong H (2004) Dietary celluloses effect on the flow of amino acid and endogenous amino acid at the terminal ileum of pig. Acta Veterinaria et Zootechnica Sinica 35(4):473–476

  33. Li P, Yin YL, Li D, Kim SW, Wu G (2007) Amino acids and immune function. Br J Nutr 98(2):237–252. doi:10.1017/S000711450769936X

  34. Li TJ, Dai QZ, Yin YL, Zhang J, Huang RL, Ruan Z, Deng Z, Xie M (2008) Dietary starch sources affect net portal appearance of amino acids and glucose in growing pigs. Animal 2(5):723–729. doi:10.1017/S1751731108001614

  35. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16(11):26087–26124. doi:10.1111/j.1523-1755.2002.kid558.x

  36. Liu G, Yu L, Fang J, Hu CA, Yin J, Ni H, Ren W, Duraipandiyan V, Chen S, Al-Dhabi NA, Yin Y (2017) Methionine restriction on oxidative stress and immune response in dss-induced colitis mice. Oncotarget 8 (27):44511–44520. doi:10.18632/oncotarget.17812

  37. Libao-Mercado AJ, Yin Y, Van EJ, de Lange CF (2006) True ileal amino acid digestibility and endogenous ileal amino acid losses in growing pigs fed wheat shorts- or casein-based diets. J Anim Sci 84(6):1351–1361

  38. Lowe F (2014) Biomarkers of oxidative stress. In: Laher I (ed) Systems biology of free radicals and antioxidants, vol 2, 1st edn. Springer, Berlin, pp 65–87 (chap 3)

  39. Mackay DS, Brophy JD, Mcbreairty LE, Mcgowan RA, Bertolo RF (2012) Intrauterine growth restriction leads to changes in sulfur amino acid metabolism, but not global DNA methylation. Yucatan miniature piglets. J Nutr Biochem 23(9):1121–1127. doi:10.1016/j.jnutbio.2011.06.005

  40. Maddineni S, Nichenametla S, Sinha R, Wilson RP, Richie JP (2013) Methionine restriction affects oxidative stress and glutathione-related redox pathways in the rat. Exp Biol Med 238(4):392–399. doi:10.1177/1535370213477988

  41. Maddocks ODK, Labuschagne CF, Adams PD, Vousden KH (2016) Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell 61(2):210–221. doi:10.1016/j.molcel.2015.12.014

  42. Manji H, Kato T, Di PN, Ness S, Beal MF, Krams M, Chen G (2012) Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci 13(5):293–307. doi:10.1038/nrn3229

  43. Molero-Luis M, Serrano M, O’Callaghan MM, Sierra C, Pérez-Dueñas B, García-Cazorla A, Artuch R (2015) Clinical, etiological and therapeutic aspects of cerebral folate deficiency. Expert Rev Neurother 15(7):793–802. doi:10.1586/14737175.2015.1055322

  44. Nicholson JK, Lindon JC, Holmes E (2008) ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29(11):1181–1189. doi:10.1080/004982599238047

  45. Nimse SB, Pal D (2015) Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv 5(35):27986–28006. doi:10.1039/C4RA13315C

  46. Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D (2012) l-Methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 169(12):1267. doi:10.1176/appi.ajp.2012.11071114

  47. Patra RC, Swarup D, Dwivedi SK (2001) Antioxidant effects of α tocopherol, ascorbic acid and l-methionine on lead induced oxidative stress to the liver, kidney and brain in rats. Toxicology 162(2):81–88

  48. Pirkov I, Norbeck J, Gustafsson L, Albers E (2008) A complete inventory of all enzymes in the eukaryotic methionine salvage pathway. FEBS J 275(16):4111–4120. doi:10.1111/j.1742-4658.2008.06552.x

  49. Rezzi S, Ramadan Z, Fay LB, Kochhar S (2007) Nutritional metabonomics: applications and perspectives. J Proteome Res 6(2):513–525. doi:10.1021/pr060522z

  50. Riedijk MA, Stoll B, Chacko S, Schierbeek H, Sunehag AL, van Goundoever JB, Burrin DG (2007) Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract. Proc Natl Acad Sci USA 104(9):3408–3413. doi:10.1073/pnas.0607965104

  51. Romano A, Serviddio G, Calcagnini S, Villani R, Giudetti AM, Cassano T, Gaetani S (2017) Linking lipid peroxidation and neuropsychiatric disorders: focus on 4-hydroxy-2-nonenal. Free Radic Biol Med 111:281–293. doi:10.1016/j.freeradbiomed.2016.12.046

  52. Scola G, Kim HK, Young LT, Andreazza AC (2013) A fresh look at complex I in microarray data: clues to understanding disease-specific mitochondrial alterations in bipolar disorder. Biol Psychiatry 73(2):e4–e5. doi:10.1016/j.biopsych.2012.06.028

  53. Serviddio G, Romano AD, Cassano T, Bellanti F, Altomare E, Vendemiale G (2011) Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases. Curr Pharm Des 17(20):2036–2055

  54. Shoveller AK, Brunton JA, Pencharz PB, Bal RO (2003) The methionine requirement is lower in neonatal piglets fed parenterally than in those fed enterally. J Nutr 133(5):1390–1397

  55. Soares MS, Oliveira PS, Debom GN, da Silveira Mattos B, Polachini CR, Baldissarelli J, Morsch VM, Schetinger MR, Tavares RG, Stefanello FM, Spanevello RM (2017) Chronic administration of methionine and/or methionine sulfoxide alters oxidative stress parameters and ALA-D activity in liver and kidney of young rats. Amino Acids 49(1):129–138. doi:10.1007/s00726-016-2340-y

  56. Stefanello FM, Kreutz F, Scherer EBS, Breier AC, Vianna LP, Trindade VMT, Wyse ATS (2007) Reduction of gangliosides, phospholipids and cholesterol content in cerebral cortex of rats caused by chronic hypermethioninemia. Int J Dev Neurosci 25(7):473–477. doi:10.1016/j.ijdevneu.2007.08.004

  57. Stefanello FM, Matte C, Pederzolli CD, Kolling J, Mescka CP, Lamers ML, de Assis AM, Perry ML, dos Santos MF, Dutra CS, Wyse ATS (2009) Hypermethioninemia provokes oxidative damage and histological changes in liver of rats. Biochimie 91(8):961–968. doi:10.1016/j.biochi.2009.04.018

  58. Stoll B, Burrin DG, Henry J, Yu H, Jahoor F, Reeds PJ (1999) Substrate oxidation by the portal drained viscera of fed piglets. Am J Physiol 277(1 Pt 1):E168–E175

  59. Stover PJ, Durga J, Field MS (2017) Folate nutrition and blood–brain barrier dysfunction. Curr Opin Biotechnol 44:146–152. doi:10.1016/j.copbio.2017.01.006

  60. Swain BK, Johri TS (2000) Effect of supplemental methionine, choline and their combinations on the performance and immune response of broilers. Br Poult Sci 41(1):83–88

  61. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. Cancer J Clin 65(2):87–108. doi:10.3322/caac.21262

  62. Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J (2003) The atherogenic effect of excess methionine intake. Proc Natl Acad Sci USA 100(25):15089–15094. doi:10.1073/pnas.2436385100

  63. Trumbo PR (2008) Challenges with using chronic disease endpoints in setting dietary reference intakes. Nutr Rev 66(8):459–464. doi:10.1111/j.1753-4887.2008.00077.x

  64. Tsiagbe VK, Cook ME, Harper AE, Sunde ML (1987) Enhanced immune-responses in broiler chicks fed methionine-supplemented diets. Poult Sci 66(7):1147–1154

  65. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74. doi:10.2174/157015909787602823

  66. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):1–40. doi:10.1016/j.cbi.2005.12.009

  67. Vieira SL, Lemme A, Goldenberg DB, Brugalli I (2004) Responses of growing broilers to diets with increased sulfur amino acids to lysine ratios at two dietary protein levels. Poult Sci 83(8):1307–1313

  68. Wang W, Shi C, Zhang J, Gu W, Li T, Gen M, Chu W, Huang R, Liu Y, Hou Y (2009) Molecular cloning, distribution and ontogenetic expression of the oligopeptide transporter PepT1 mRNA in Tibetan suckling piglets. Amino Acids 37(4):593–601. doi:10.1007/s00726-008-0178-7

  69. Wu G, Bazer FW, Davis TA, Jaeger LA, Johnson GA, Kim SW, Knabe DA, Meininger CJ, Spencer TE, Yin YL (2007) Important roles for arginine family amino acids in swine nutrition and production. Livest Sci 112(1–2):8–22. doi:10.1016/j.livsci.2007.07.003

  70. Xiao Q, Freedman ND, Ren J, Hollenbeck AR, Abnet CC, Park Y (2014) Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer 110(5):1328–1333. doi:10.1038/bjc.2014.17

  71. Yao JK, Keshavan MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxid Redox Sign 15(7):2011–2035. doi:10.1089/ars.2010.3603

  72. Yin YL, Bie T (2010) Manipulation of dietary nitrogen, amino acids and phosphorous to reduce environmental impact of swine production and enhance animal health. J Food Agric Environ 8(3):447–462

  73. Yin YL, Deng ZY, Huang HL, Zhong HY, Hou ZP, Gong J, Liu Q (2004) Nutritional and health functions of carbohydrate for pigs. J Anim Feed Sci 13(4):523–538. doi:10.22358/jafs/67623/2004

  74. Yin FG, Zhang ZZ, Ju H, Yin YL (2010) Digestion rate of dietary starch affects systemic circulation of amino acids in weaned pigs. Br J Nutr 103(10):1404. doi:10.1017/S0007114509993321

  75. Zhou XH, He LQ, Wan D, Yang HS, Yao K, Wu GY, Wu X, Yin YL (2016) Methionine restriction on lipid metabolism and its possible mechanisms. Amino Acids 48(7):1533–1540. doi:10.1007/s00726-016-2247-7

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This research was supported by National Natural Science Foundation of China (No. 31772642), International Partnership Program of Chinese Academy of Sciences (161343KYSB20160008), National Key Research and Development Program of China (2016YFD0500504), and Chinese Academy of Sciences visiting professorship for senior international scientists Grant no. 2016VBB007.

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Correspondence to Gang Liu.

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Handling Editors: C.-A.A. Hu, Y. Yin, Y. Hou, G. Wu, Y. Teng.

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Martínez, Y., Li, X., Liu, G. et al. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids 49, 2091–2098 (2017).

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  • Methionine
  • Mammalian
  • Endogenous antioxidant enzyme
  • ROS
  • Cancer
  • Disease