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Excess S-adenosylmethionine inhibits methylation via catabolism to adenine

Fukumoto, Kazuki Ito, Kakeru Saer, Benjamin Taylor, George Ye, Shiqi Yamano, Mayu Toriba, Yuki Hayes, Andrew Okamura, Hitoshi Fustin, Jean-Michel 京都大学 DOI:10.1038/s42003-022-03280-5

2022

概要

The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.

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参考文献

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Cantoni, G. L. Biological methylation: selected aspects. Annu Rev. Biochem 44,

435–451 (1975).

Froese, D. S., Fowler, B. & Baumgartner, M. R. Vitamin B12, folate, and the

methionine remethylation cycle-biochemistry, pathways, and regulation. J.

Inherit. Metab. Dis. 42, 673–685 (2019).

Poirier, L. A., Herrera, L. A. C. & Wise, C. in Regulatory Research Perspectives

Vol. 3 (National Center for Toxicological Research, 2003).

Potter, J. D. Methyl supply, methyl metabolizing enzymes and colorectal

neoplasia. J. Nutr. 132, 2410S–2412S (2002).

Ziegler, R. G., Weinstein, S. J. & Fears, T. R. Nutritional and genetic

inefficiencies in one-carbon metabolism and cervical cancer risk. J. Nutr. 132,

2345S–2349S (2002).

Longnecker, D. S. Abnormal methyl metabolism in pancreatic toxicity and

diabetes. J. Nutr. 132, 2373S–2376S (2002).

Aavik, E., Babu, M. & Yla-Herttuala, S. DNA methylation processes in

atheosclerotic plaque. Atherosclerosis 281, 168–179 (2019).

Troen, A. M., Lutgens, E., Smith, D. E., Rosenberg, I. H. & Selhub, J. The

atherogenic effect of excess methionine intake. Proc. Natl Acad. Sci. USA 100,

15089–15094 (2003).

Malinowska, A. & Chmurzynska, A. Polymorphism of genes encoding

homocysteine metabolism-related enzymes and risk for cardiovascular disease.

Nutr. Res 29, 685–695 (2009).

Rader, J. I. Folic acid fortification, folate status and plasma homocysteine. J.

Nutr. 132, 2466S–2470S (2002).

Lippi, G. & Plebani, M. Hyperhomocysteinemia in health and disease: where

we are now, and where do we go from here. Clin. Chem. Lab. Med. 50,

2075–2080 (2012).

Bottiglieri, T. et al. Cerebrospinal fluid S-adenosylmethionine in depression

and dementia: effects of treatment with parenteral and oral

S-adenosylmethionine. J. Neurol. Neurosurg. Psychiatry 53, 1096–1098 (1990).

Papakostas, G. I., Alpert, J. E. & Fava, M. S-adenosyl-methionine in

depression: a comprehensive review of the literature. Curr. Psychiatry Rep. 5,

460–466 (2003).

Hardy, M. L. et al. S-adenosyl-L-methionine for treatment of depression,

osteoarthritis, and liver disease. Evid. Rep. Technol. Assess (Summ) 64, 1–3 (2003).

Mischoulon, D. et al. A double-blind, randomized, placebo-controlled clinical

trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major

depressive disorder. J. Clin. Psychiatry 75, 370–376 (2014).

Gerbarg, P. L., Muskin, P. R., Bottiglieri, T. & Brown, R. P. Failed studies

should not be used to malign good treatments. J. Clin. Psychiatry 75, e1328

(2014).

Mischoulon, D. et al. Dr. Mischoulon and colleagues reply. J. Clin. Psychiatry

75, e1328–e1329 (2014).

Sarris, J. et al. Is S-adenosyl methionine (SAMe) for depression only effective

in males? A re-analysis of data from a randomized clinical trial.

Pharmacopsychiatry 48, 141–144 (2015).

ARTICLE

19. Sakurai, H. et al. Dose increase of S-Adenosyl-Methionine and escitalopram in

a randomized clinical trial for major depressive disorder. J. Affect Disord. 262,

118–125 (2020).

20. Guo, T., Chang, L., Xiao, Y. & Liu, Q. S-adenosyl-L-methionine for the

treatment of chronic liver disease: a systematic review and meta-analysis. PLoS

ONE 10, e0122124 (2015).

21. Najm, W. I., Reinsch, S., Hoehler, F., Tobis, J. S. & Harvey, P. W. S-adenosyl

methionine (SAMe) versus celecoxib for the treatment of osteoarthritis

symptoms: a double-blind cross-over trial. [ISRCTN36233495]. BMC

Musculoskelet. Disord. 5, 6 (2004).

22. Loehrer, F. M., Schwab, R., Angst, C. P., Haefeli, W. E. & Fowler, B. Influence

of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, Sadenosylhomocysteine, homocysteine and methionine in healthy humans. J.

Pharm. Exp. Ther. 282, 845–850 (1997).

23. Sauer, J., Mason, J. B. & Choi, S. W. Too much folate: a risk factor for cancer

and cardiovascular disease? Curr. Opin. Clin. Nutr. Metab. Care 12, 30–36

(2009).

24. Mosca, L. et al. Effects of SadenosylLmethionine on the invasion and

migration of head and neck squamous cancer cells and analysis of the

underlying mechanisms. Int. J. Oncol. 56, 1212–1224 (2020).

25. Ilisso, C. P. et al. S-Adenosylmethionine regulates apoptosis and autophagy in

MCF-7 breast cancer cells through the modulation of specific microRNAs.

Cancer Cell Int. 18, 197 (2018).

26. Wang, Y., Sun, Z. & Szyf, M. S-adenosyl-methionine (SAM) alters the

transcriptome and methylome and specifically blocks growth and invasiveness

of liver cancer cells. Oncotarget 8, 111866–111881 (2017).

27. Fustin, J. M. et al. RNA-methylation-dependent RNA processing controls the

speed of the circadian clock. Cell 155, 793–806 (2013).

28. Fustin, J. M. et al. Methylation deficiency disrupts biological rhythms from

bacteria to humans. Commun. Biol. 3, 211 (2020).

29. Yoo, S. H. et al. PERIOD2::LUCIFERASE real-time reporting of circadian

dynamics reveals persistent circadian oscillations in mouse peripheral tissues.

Proc. Natl Acad. Sci. USA 101, 5339–5346 (2004).

30. Lin, D. W., Chung, B. P. & Kaiser, P. S-adenosylmethionine limitation induces

p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1. J. Cell

Sci. 127, 50–59 (2014).

31. Haws, S. A. et al. Methyl-metabolite depletion elicits adaptive responses to

support heterochromatin stability and epigenetic persistence. Mol. Cell 78,

210–223 e218 (2020).

32. Shima, H. et al. S-Adenosylmethionine synthesis is regulated by selective

N(6)-adenosine methylation and mRNA degradation involving METTL16

and YTHDC1. Cell Rep. 21, 3354–3363 (2017).

33. Baggs, J. E. et al. Network features of the mammalian circadian clock. PLoS

Biol. 7, e52 (2009).

34. Matsuo, Y. & Greenberg, D. M. A crystalline enzyme that cleaves homoserine

and cystathionine. I. Isolation procedure and some physicochemical

properties. J. Biol. Chem. 230, 545–560 (1958).

35. Kozich, V. et al. Cystathionine beta-synthase mutations: effect of mutation

topology on folding and activity. Hum. Mutat. 31, 809–819 (2010).

36. Zwighaft, Z. et al. Circadian clock control by polyamine levels through a

mechanism that declines with age. Cell Metab. 22, 874–885 (2015).

37. Avila, M. A., Garcia-Trevijano, E. R., Lu, S. C., Corrales, F. J. & Mato, J. M.

Methylthioadenosine. Int. J. Biochem. cell Biol. 36, 2125–2130 (2004).

38. Tang, B., Lee, H. O., An, S. S., Cai, K. Q. & Kruger, W. D. Specific targeting of

MTAP-deleted tumors with a combination of 2′-fluoroadenine and 5′methylthioadenosine. Cancer Res 78, 4386–4395 (2018).

39. Appleby, T. C., Erion, M. D. & Ealick, S. E. The structure of human 5′-deoxy5′-methylthioadenosine phosphorylase at 1.7 A resolution provides insights

into substrate binding and catalysis. Structure 7, 629–641 (1999).

40. Kamatani, N. & Carson, D. A. Dependence of adenine production upon

polyamine synthesis in cultured human lymphoblasts. Biochimica et.

Biophysica Acta 675, 344–350 (1981).

41. Hershfield, M. S. & Seegmiller, J. E. Regulation of de novo purine biosynthesis

in human lymphoblasts. Coordinate control of proximal (rate-determining)

steps and the inosinic acid branch point. J. Biol. Chem. 251, 7348–7354

(1976).

42. Aronow, L. Reversal of adenine toxicity by pyrimidine mucleosides.

Biochimica et. Biophysica Acta 47, 184–185 (1961).

43. Matsuo, T. et al. Control mechanism of the circadian clock for timing of cell

division in vivo. Science 302, 255–259 (2003).

44. Snyder, F. F., Hershfield, M. S. & Seegmiller, J. E. Cytotoxic and metabolic

effects of adenosine and adenine on human lymphoblasts. Cancer Res. 38,

2357–2362 (1978).

45. Hershfield, M. S., Snyder, F. F. & Seegmiller, J. E. Adenine and adenosine are

toxic to human lymphoblast mutants defective in purine salvage enzymes.

Science 197, 1284–1287 (1977).

46. Cantoni, G. L. The role of S-adenosylhomocysteine in the biological utilization

of S-adenosylmethionine. Prog. Clin. Biol. Res. 198, 47–65 (1985).

COMMUNICATIONS BIOLOGY | (2022)5:313 | https://doi.org/10.1038/s42003-022-03280-5 | www.nature.com/commsbio

13

ARTICLE

A Self-archived copy in

Kyoto University Research Information Repository

https://repository.kulib.kyoto-u.ac.jp

COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-022-03280-5

47. Schanche, J. S., Schanche, T., Ueland, P. M. & Montgomery, J. A.

Inactivation and reactivation of intracellular S-adenosylhomocysteinase in

the presence of nucleoside analogues in rat hepatocytes. Cancer Res. 44,

4297–4302 (1984).

48. Ueland, P. M. S-Adenosylhomocysteinase from mouse liver. Inactivation of

the enzyme in the presence of metabolites. Int. J. Biochem. 14, 207–213 (1982).

49. Regenass, U. et al. CGP 48664, a new S-adenosylmethionine decarboxylase

inhibitor with broad spectrum antiproliferative and antitumor activity. Cancer

Res. 54, 3210–3217 (1994).

50. Pegg, A. E. Mammalian polyamine metabolism and function. IUBMB Life 61,

880–894 (2009).

51. Basu, I. et al. A transition state analogue of 5’-methylthioadenosine

phosphorylase induces apoptosis in head and neck cancers. J. Biol. Chem. 282,

21477–21486 (2007).

52. Evans, G. B. et al. Second generation transition state analogue inhibitors of

human 5′-methylthioadenosine phosphorylase. J. Med Chem. 48, 4679–4689

(2005).

53. Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the

PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218

(2016).

54. Hong, S. et al. Type II protein arginine methyltransferase 5 (PRMT5) is

required for circadian period determination in Arabidopsis thaliana. Proc.

Natl Acad. Sci. USA 107, 21211–21216 (2010).

55. Bigaud, E. & Corrales, F. J. Methylthioadenosine (MTA) regulates liver cells

proteome and methylproteome: implications in liver biology and disease. Mol.

Cell Proteom. 15, 1498–1510 (2016).

56. Fustin, J. M. et al. Two Ck1delta transcripts regulated by m6A methylation

code for two antagonistic kinases in the control of the circadian clock. Proc.

Natl Acad. Sci. USA 115, 5980–5985 (2018).

57. Valekunja, U. K. et al. Histone methyltransferase MLL3 contributes to

genome-scale circadian transcription. Proc. Natl Acad. Sci. USA 110,

1554–1559 (2013).

58. Katada, S. & Sassone-Corsi, P. The histone methyltransferase MLL1 permits

the oscillation of circadian gene expression. Nat. Struct. Mol. Biol. 17,

1414–1421 (2010).

59. Greco, C. M. et al. S-adenosyl-l-homocysteine hydrolase links methionine

metabolism to the circadian clock and chromatin remodeling. Sci. Adv. 6,

https://doi.org/10.1126/sciadv.abc5629 (2020).

60. Regestein, Q. R. & Monk, T. H. Delayed sleep phase syndrome: a review of its

clinical aspects. Am. J. Psychiatry 152, 602–608 (1995).

61. Jones, C. R. et al. Familial advanced sleep-phase syndrome: A short-period

circadian rhythm variant in humans. Nat. Med. 5, 1062–1065 (1999).

62. Hershfield, M. S. & Krodich, N. M. S-adenosylhomocysteine hydrolase is an

adenosine-binding protein: a target for adenosine toxicity. Science 202,

757–760 (1978).

63. Kredich, N. M. & Martin, D. V. Jr. Role of S-adenosylhomocysteine in

adenosinemediated toxicity in cultured mouse T lymphoma cells. Cell 12,

931–938 (1977).

64. Hershfield, M. S. Genotype is an important determinant of phenotype in

adenosine deaminase deficiency. Curr. Opin. Immunol. 15, 571–577 (2003).

65. Nyhan, W. L. Disorders of purine and pyrimidine metabolism. Mol. Genet.

Metab. 86, 25–33 (2005).

66. Dillman, R. O. Pentostatin (Nipent) in the treatment of chronic lymphocyte

leukemia and hairy cell leukemia. Expert Rev. Anticancer Ther. 4, 27–36

(2004).

67. Bachmann, V. et al. Functional ADA polymorphism increases sleep depth and

reduces vigilant attention in humans. Cereb. Cortex 22, 962–970 (2012).

68. Retey, J. V. et al. A functional genetic variation of adenosine deaminase affects

the duration and intensity of deep sleep in humans. Proc. Natl Acad. Sci. USA

102, 15676–15681 (2005).

69. Diwan, V., Brown, L. & Gobe, G. C. Adenine-induced chronic kidney disease

in rats. Nephrology 23, 5–11 (2018).

70. Motohashi, H. et al. The circadian clock is disrupted in mice with adenineinduced tubulointerstitial nephropathy. Kidney Int. 97, 728–740 (2020).

71. Myung, J. et al. The kidney clock contributes to timekeeping by the master

circadian clock. Int. J. Mol. Sci. 20, https://doi.org/10.3390/ijms20112765

(2019).

72. Zielinski, T., Moore, A. M., Troup, E., Halliday, K. J. & Millar, A. J. Strengths

and limitations of period estimation methods for circadian data. PLoS ONE 9,

e96462 (2014).

73. Soga, T. & Heiger, D. N. Amino acid analysis by capillary electrophoresis

electrospray ionization mass spectrometry. Anal. Chem. 72, 1236–1241 (2000).

74. Soga, T. et al. Quantitative metabolome analysis using capillary

electrophoresis mass spectrometry. J. Proteome Res. 2, 488–494 (2003).

75. Soga, T. et al. Simultaneous determination of anionic intermediates

for Bacillus subtilis metabolic pathways by capillary electrophoresis

electrospray ionization mass spectrometry. Anal. Chem. 74, 2233–2239 (2002).

14

76. Sugimoto, M., Wong, D. T., Hirayama, A., Soga, T. & Tomita, M. Capillary

electrophoresis mass spectrometry-based saliva metabolomics identified

oral, breast and pancreatic cancer-specific profiles. Metabolomics 6, 78–95

(2010).

77. Chong, J. & Xia, J. Using MetaboAnalyst 4.0 for metabolomics data analysis,

interpretation, and integration with other omics data. Methods Mol. Biol.

2104, 337–360 (2020).

78. Xia, J. & Wishart, D. S. Web-based inference of biological patterns, functions

and pathways from metabolomic data using MetaboAnalyst. Nat. Protoc. 6,

743–760 (2011).

79. Xia, J. & Wishart, D. S. Metabolomic data processing, analysis, and

interpretation using MetaboAnalyst. Curr. Protoc. Bioinforma. 14, 10

(2011).

80. Afgan, E. et al. The Galaxy platform for accessible, reproducible and

collaborative biomedical analyses: 2018 update. Nucleic Acids Res. 46,

W537–W544 (2018).

81. Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for

Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).

82. Frankish, A. et al. GENCODE reference annotation for the human and mouse

genomes. Nucleic Acids Res. 47, D766–D773 (2019).

83. Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low

memory requirements. Nat. Methods 12, 357–360 (2015).

84. Pertea, M., Kim, D., Pertea, G. M., Leek, J. T. & Salzberg, S. L. Transcript-level

expression analysis of RNA-seq experiments with HISAT, StringTie and

Ballgown. Nat. Protoc. 11, 1650–1667 (2016).

85. Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome

from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015).

86. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor

package for differential expression analysis of digital gene expression data.

Bioinformatics 26, 139–140 (2010).

87. Liu, R. et al. Why weight? Modelling sample and observational level variability

improves power in RNA-seq analyses. Nucleic Acids Res. 43, e97 (2015).

88. Reich, M. et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).

Acknowledgements

This work was supported by the Medical Research Council (Future Leaders Fellowship

MR/S031812/1), by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant-in-aid for Scientific Research on Innovative Areas 26116713

(J.-M.F.); Grant-in-aid for Young Scientists 26870283 (J.-M.F.); Grant-in-aid for

Scientific Research A 18H04015 (H.O.)), and by a grant for Core Research for Evolutional Science and Technology, Japan Science and Technology Agency CREST/

JPMJCR14W3 (H.O.). J.-M.F. was also supported by grants from the Kato Memorial

Bioscience Foundation, the Senri Life Science Foundation (S-26003), the Mochida

Memorial Foundation for Medical and Pharmaceutical Research, and the Kyoto

University internal grant ISHIZUE. We thank Dr. Carolina Greco for the HA-AHCY

vector, and Prof Mark Helm for his advice on methylated nucleotides quantification.

The authors would like to acknowledge the help of Dr. Peter Briggs for the use of the

local Galaxy service provided by the Bioinformatics Core Facility and IT Services at

the University of Manchester.

Author contributions

J.-M.F. designed the project, performed experiments, and wrote the paper. K.F., K.I.,

S.Y., M.Y., and Y.T. contributed to the experiments shown in Figs. 1–3. B.S. contributed to the experiments shown in Figs. 3–5. G.T. produced MS data shown in

Fig. 4c. A.H. generated raw RNAseq data used in Fig. 5b. H.O. contributed to the

design of the project.

Competing interests

The authors declare no competing interests.

Additional information

Supplementary information The online version contains supplementary material

available at https://doi.org/10.1038/s42003-022-03280-5.

Correspondence and requests for materials should be addressed to Hitoshi Okamura or

Jean-Michel Fustin.

Peer review information Communications Biology thanks the anonymous reviewers for

their contribution to the peer review of this work. Primary Handling Editors: ZhengJiang Zhu and Gene Chong. Peer reviewer reports are available.

Reprints and permission information is available at http://www.nature.com/reprints

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations.

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