Original Paper | Published:

The unusual amino acid L-ergothioneine is a physiologic cytoprotectant

Cell Death and Differentiation volume 17, pages 11341140 (2010) | Download Citation

Edited by RA Knight

Subjects

Abstract

Ergothioneine (ET) is an unusual sulfur-containing derivative of the amino acid, histidine, which is derived exclusively through the diet. Although ET was isolated a century ago, its physiologic function has not been clearly established. Recently, a highly specific transporter for ET (ETT) was identified in mammalian tissues, which explains abundant tissue levels of ET and implies a physiologic role. Using RNA interference, we depleted cells of its transporter. Cells lacking ETT are more susceptible to oxidative stress, resulting in increased mitochondrial DNA damage, protein oxidation and lipid peroxidation. ETT is concentrated in mitochondria, suggesting a specific role in protecting mitochondrial components such as DNA from oxidative damage associated with mitochondrial generation of superoxide. In combating cytotoxic effects of pyrogallol, a known superoxide generator, ET is as potent as glutathione. Because of its dietary origin and the toxicity associated with its depletion, ET may represent a new vitamin whose physiologic roles include antioxidant cytoprotection.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    . Sur une base nouvelle retiree du siegle ergote, l' ergothioneine. Compt Rende 1909; 49: 22–224.

  2. 2.

    , . Biosynthesis of ergothioneine and hercynine by mycobacteria. J Bacteriol 1964; 87: 852–862.

  3. 3.

    . Biosynthesis of ergothioneine and hercynine by fungi and Actinomycetales. J Bacteriol 1970; 103: 475–478.

  4. 4.

    , , . The biosynthesis of Ergothioneine. J Biol Chem 1957; 224: 871–877.

  5. 5.

    , . The reaction sequence in Ergothioneine biosynthesis: hercynine as an intermediate. J Biol Chem 1962; 237: 1615–1618.

  6. 6.

    , , , . Identification and quantification of ergothioneine in cultivated mushrooms by liquid chromatography-mass spectroscopy. Int J Med Mush 2006; 8: 215–222.

  7. 7.

    , , . Dietary sources and antioxidant effects of ergothioneine. J Agric Food Chem 2007; 55: 6466–6474.

  8. 8.

    . Ergothioneine. Vitamin Horm 1959; 17: 155–204.

  9. 9.

    , , . Ergothioneine content in normal and senile human cataractous lenses. Ind Med Res 1981; 73: 472–473.

  10. 10.

    , , , . Ergothioneine distribution in bovine and porcine ocular tissues. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1997; 117: 117–120.

  11. 11.

    . Ergothioneine as an antioxidant. Methods Enzymol 1990; 186: 310–318.

  12. 12.

    , , , , , et al. Discovery of the ergothioneine transporter. Proc Natl Acad Sci USA 2005; 102: 5256–5261.

  13. 13.

    , , , , , et al. Cloning and characterization of a novel pH-dependent organic cation transporter, OCTN1. FEBS Lett 1997; 819: 107–111.

  14. 14.

    , , , , , et al. Probing the substrate specificity of the ergothioneine transporter with methimazole, hercynine, and organic cations. Biochem Pharmacol 2007; 74: 309–316.

  15. 15.

    , , , , , et al. Structural and functional characteristics and tissue distribution pattern of OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta 2000; 1466: 315–327.

  16. 16.

    , , , , , et al. Expression of organic cation transporter OCTN1 in hematopoietic cells during erythroid differentiation. Exp Hematol 2004; 32: 1156–1162.

  17. 17.

    , , , , , et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 2003; 35: 341–348.

  18. 18.

    , , , , , et al. Functional variants of OCTN cation transporter genes are associated with Crohn's disease. Nat Genet 2004; 36: 471–475.

  19. 19.

    , , , . Increased ergothioneine tissue concentrations in carriers of the Crohn's disease risk-associated 503F variant of the organic cation transporter OCTN1. Gut 2009; 58: 312–314.

  20. 20.

    , , , , , . Ergothioneine inhibits oxidative stress and TNF-alpha induced NF-kappa B activation and interleukin-8 release in alveolar epithelial cells. Biochem Biophys Res Commun 2003; 302: 860–864.

  21. 21.

    , , , , . Mechanism of the regulation of organic cation/carnitine transporter 1(SLC22A4) by rheumatoid arthritis-associated transcriptional factor RUNX1 and inflammatory cytokines. Drug Metab Dispos 2007; 35: 394–401.

  22. 22.

    , , , , , et al. Decreased proliferation and erythroid differentiation of K562 cells by siRNA induced depression of OCTN1 (SLC22A4) transporter gene. Pharm Res 2007; 24: 1628–1635.

  23. 23.

    , , , , . Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn's disease. Gut 2005; 54: 1505–1506.

  24. 24.

    , , , , , . Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci USA 2009; 106: 1571–1576.

  25. 25.

    , . Novel localization of OCTN1, an organic cation/carntine transporter to mammalian mitochondria. Biochem Biophys Res Commun 2006; 345: 1315–1325.

  26. 26.

    , , , , , et al. Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res 2001; 61: 7015–7019.

  27. 27.

    , , , , , . Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc Natl Acad Sci USA 2003; 100: 1838–1843.

  28. 28.

    , , . Fine-mapping of DNA damage and repair in specific genomic segments. Nucleic Acids Res 1990; 18: 3823–3830.

  29. 29.

    , . A polymerase chain reaction-based method to detect cisplatin adducts in specific genes. Nucleic Acids Res 1991; 19: 6209–6214.

  30. 30.

    , , . Reactions of L-ergothioneine and some other aminothiones with 2,2′-and 4,4′-dipyridyl disulphides and of L-ergothioneine with iodoacetamide. 2-Mercaptoimidazoles, 2- and 4-thiopyridones, thiourea and thioacetamide as highly reactive neutral sulphur nucleophils. Biochem J 1974; 139: 237–242.

  31. 31.

    , , , , . L-Ergothioneine scavenges superoxide and singlet oxygen and suppresses TNF-alpha and MMP-1 expression in UV-irradiated human dermal fibroblasts. J Cosmet Sci 2005; 56: 17–27.

  32. 32.

    , , . Protection against oxidative damage and cell death by the natural antioxidant ergothioneine. Food Chem Toxicol 1999; 37: 1043–1053.

  33. 33.

    , , , , , . L-ergothioneine modulates oxidative damage in the kidney and liver of rats in vivo: studies upon the profile of polyunsaturated fatty acids. Clin Nutr 2004; 23: 183–193.

  34. 34.

    , , , , , et al. Modulation of hydrogen peroxide-induced DNA damage, MAPKs activation and cell death in PC12 by ergothioneine. Clin Nutr 2006; 25: 135–145.

  35. 35.

    , , , , , . Skin cells and tissue are capable of using L-ergothioneine as an integral component of their antioxidant defense system. Free Radic Biol Med 2009; 46: 1168–1176.

  36. 36.

    , , , , , et al. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci USA 1999; 96: 2445–2450. Erratum in: Proc Natl Acad Sci USA 1999;96:10944.

  37. 37.

    , , , . Biliverdin reductase: biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA 2002; 99: 16093–16098.

  38. 38.

    , , , , , . Studies on ergothioneine. VI. Distribution and fluctuations of ergothioneine in rats. Chem Pharm Bull (Tokyo) 1982; 30: 1760–1765.

  39. 39.

    , , , , , et al. Somatic mitochondrial DNA mutations in cortex and s ubstantia nigra in aging and Parkinson's disease. Neurobiol Aging 2004; 25: 71–81.

  40. 40.

    , . Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443: 787–795.

  41. 41.

    , , , , , et al. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 1999; 289: 768–773.

Download references

Acknowledgements

This work was supported by United States Public Health Service Grants DA00266 (to SHS) and a Research Scientist Award DA00074 (to SHS).

Author information

Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

    • B D Paul
    •  & S H Snyder
  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

    • S H Snyder
  3. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

    • S H Snyder

Authors

  1. Search for B D Paul in:

  2. Search for S H Snyder in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to S H Snyder.

Glossary

ET

ergothioneine

ETT

ergothioneine Transporter

DNPH

2,4-dinitrophenylhydrazine

MDA

malondialdehyde

mtDNA

mitochondrial DNA

MTT

3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OCTN1

novel organic cation transporter 1

TBARS

thiobarbituric acid reactive substances

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/cdd.2009.163

Further reading