Ergothioneine

Ergothioneine
Names
Preferred IUPAC name
(2S)-3-(2-Sulfanylidene-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylazaniumyl)propanoate
Other names
L-Ergothioneine; (+)-Ergothioneine; Thiasine; Sympectothion; Ergothionine; Erythrothioneine; Thiolhistidinebetaine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.007.131
KEGG
UNII
  • InChI=1S/C9H15N3O2S/c1-12(2,3)7(8(13)14)4-6-5-10-9(15)11-6/h5,7H,4H2,1-3H3,(H2-,10,11,13,14,15)/t7-/m0/s1 Y
    Key: SSISHJJTAXXQAX-ZETCQYMHSA-N Y
  • InChI=1/C9H15N3O2S/c1-12(2,3)7(8(13)14)4-6-5-10-9(15)11-6/h5,7H,4H2,1-3H3,(H2-,10,11,13,14,15)/t7-/m0/s1
    Key: SSISHJJTAXXQAX-ZETCQYMHBA
  • C[N+](C)(C)C(CC1=CNC(=S)N1)C(=O)[O-]
  • S=C1N\C(=C/N1)C[C@@H](C([O-])=O)[N+](C)(C)C
Properties
C9H15N3O2S
Molar mass 229.30 g/mol
Appearance white solid
Melting point 275 to 277 °C (527 to 531 °F; 548 to 550 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Ergothioneine[1] (EGT) is a naturally occurring amino acid and is a thiourea derivative of histidine, containing a sulfur atom on the imidazole ring.[2] This compound occurs in relatively few organisms, notably actinomycetota, cyanobacteria, and certain fungi.[3][4] Ergothioneine was discovered by Charles Tanret in 1909 and named after the ergot fungus from which it was first purified,[5] with its structure being determined in 1911.[6][7]

In humans, ergothioneine is acquired exclusively through the diet and accumulates in erythrocytes, bone marrow, liver, kidney, seminal fluid, and eyes.[8] Although the effect of ergothioneine in vivo is under preliminary research, its physiological role in humans is unknown.[8] Ergothioneine is sold as a dietary supplement.[9]

Metabolism and sources

Ergothioneine has been found in bacteria, plants, and animals, sometimes at high (millimolar) levels relative to the environment.[10] Foods found to contain ergothioneine include liver, kidney, black beans, kidney bean, and oat bran, with the highest levels in bolete and oyster mushrooms, especially in Pleurotus citrinopileatus.[10][11] Levels can be variable, even within species and some tissues can contain much more than others. In the human body, the largest amounts of ergothioneine are found in erythrocytes, eye lens, semen,[7] and skin.[12]

Although many species contain ergothioneine, only a few make it; the others absorb it from their diet or, in the case of plants, from their environment.[13] Biosynthesis has been detected in Actinomycetota, such as Mycobacterium smegmatis and certain fungi, such as Neurospora crassa (red bread mold)[3] and Schizosaccharomyces pombe (fission yeast).[14]

Other species of bacteria, such as Bacillus subtilis, Escherichia coli, Proteus vulgaris, and Streptococcus, as well as fungi in the Saccharomycotina cannot make ergothioneine.[15][16]

Biosynthetic pathway

The metabolic pathway to produce ergothioneine starts with the methylation of histidine to produce histidine betaine (hercynine). The sulfur atom is then incorporated from cysteine.[10][17] The biosynthetic genes of ergothioneine have been described in detail for Mycobacterium smegmatis,[18] Neurospora crassa,[19] Schizosaccharomyces pombe (with homologues in Aspergillus, a genus important in food fermentation),[14] and Caldithrix abyssi.[20]

Different groups of organisms use different approaches to sulfur-addition. Aerobic bacteria and fungi use an O2-dependent reaction that is catalyzed by a mononuclear non-heme iron enzyme, with cysteine or γ-glutamylcysteine as the sulfur source. Green sulfur bacteria and some archaea use a rhodanese-like sulfur transferase to perform oxidative polar substitution. Caldithrix uses a metallopterin-dependent bifunctional enzyme that combines an N-terminal domain similar to a tungsten-dependent acetylene hydratase and a C-terminal cysteine desulfurase domain. Homologs of the Caldithrix system are found in anaerobic bacteria and some archaea.[20]

Industrial sources

Mass production of EGT can be achieved by microbial fermentation, i.e. culturing of microbes. The highest productivities are derived from microbes that have undergone genetically engineering to overexpress the biosynthetic pathway, either a native version (if the microbe natively makes ergothioneine) or foreign (transgenic) version. Escherichia coli and Saccharomyces cerevisiae (baker's yeast), two species commonly used in bio-engineering but unable to natively produce EGT, can reach EGT concentrations of 5400 mg/L and 2390 mg/L respectively for their culture media: around a hundred times of what non-modified microbes can achieve.[21] In 2025, an even higher concentration of 7200 mg/L was achieved with E. coli without requiring the feeding of expensive methionine (methyl source) or cysteine by adding genes to have the bacteria make its own.[22]

Structure

Ergothioneine is a thiourea derivative of the betaine of histidine and contains a sulfur atom bonded to the 2-position of the imidazole ring.[23] Typical of thioureas, ergothioneine is less reactive than typical thiols such as glutathione towards alkylating agents like maleimides. It also resists oxidation by air.[10] However, ergothioneine can be slowly oxidized over several days to the disulfide form in acidic solutions.[24]

Ergothioneine derivatives

Various derivatives of ergothioneine have been reported in the literature, such as S-methyl-ergothioneine[25] or selenium-containing selenoneine.[26] The latter is made using the same biosynthetic pathway as ergothioneine when selenocysteine is present.[14]

Preliminary research

Although ergothioneine is under preliminary research, its physiological role in vivo has not been determined.[2][8]

Mammals use the OCTN1 transporter to move ergothioneine into cells. Knockout of this gene in mouse and zebrafish models produces no substantial overt defect, though stress does amplify the differences.[8]

Safe intake levels

The Panel on Dietetic Products for the European Food Safety Authority reported safe daily limits of 2.82 mg/kg of body weight for infants, 3.39 mg/kg for small children, and 1.31 mg/kg for adults, including pregnant and breastfeeding women.[9]

See also

References

  1. ^ Borodina, I; Kenny, LC; McCarthy, CM; Paramasivan, K; Pretorius, E; Roberts, TJ; van der Hoek, S; Kell, DB (2020). "The biology of ergothioneine, an antioxidant nutraceutical". Nutr Res Rev. 33 (2): 190–217. doi:10.1017/S0954422419000301. PMC 7653990. PMID 32051057.
  2. ^ a b "Ergothioneine". PubChem, National Center for Biotechnology Information, US National Library of Medicine. 2 November 2019. Retrieved 7 November 2019.
  3. ^ a b Fahey RC (2001). "Novel thiols of prokaryotes". Annual Review of Microbiology. 55: 333–56. doi:10.1146/annurev.micro.55.1.333. PMID 11544359.
  4. ^ Pfeiffer C, Bauer T, Surek B, Schömig E, Gründemann D (2011). "Cyanobacteria produce high levels of ergothioneine". Food Chemistry. 129 (4): 1766–1769. Bibcode:2011FoodC.129.1766P. doi:10.1016/j.foodchem.2011.06.047.
  5. ^ Tanret, C. (1909). "Sur une base nouvelle retirée du seigle ergoté: l'ergothioneine". Comptes rendus hebdomadaires des séances de l'Académie des sciences (in French). 149: 222-224.
  6. ^ Barger, G.; Erwins, A.J. (1911). "The constitution of ergothioneine: a betaine related to histidine". Journal of the Chemical Society, Transactions. 99: 2336–2341. doi:10.1039/CT9119902336.
  7. ^ a b Mann T, Leone E (January 1953). "Studies on the metabolism of semen. VIII. Ergothioneine as a normal constituent of boar seminal plasma; purification and crystallization; site of formation and function". The Biochemical Journal. 53 (1): 140–8. doi:10.1042/bj0530140. PMC 1198115. PMID 13032046.
  8. ^ a b c d Cheah, Irwin K.; Halliwell, Barry (2021-01-26). "Ergothioneine, recent developments". Redox Biology. 42 101868. doi:10.1016/j.redox.2021.101868. ISSN 2213-2317. PMC 8113028. PMID 33558182.
  9. ^ a b Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, et al. (November 2017). "Statement on the safety of synthetic l-ergothioneine as a novel food - supplementary dietary exposure and safety assessment for infants and young children, pregnant and breastfeeding women". EFSA Journal. 15 (11): e05060. doi:10.2903/j.efsa.2017.5060. PMC 7010164. PMID 32625352.
  10. ^ a b c d Ey J, Schömig E, Taubert D (August 2007). "Dietary sources and antioxidant effects of ergothioneine". Journal of Agricultural and Food Chemistry. 55 (16): 6466–74. Bibcode:2007JAFC...55.6466E. doi:10.1021/jf071328f. PMID 17616140.
  11. ^ Kalač P. Edible Mushrooms. Chapter 4 - Health-Stimulating Compounds and Effects. pp 137-153. Academic Press, 2016. ISBN 9780128044551 doi:10.1016/B978-0-12-804455-1.00004-7
  12. ^ Markova NG, Karaman-Jurukovska N, Dong KK, Damaghi N, Smiles KA, Yarosh DB (April 2009). "Skin cells and tissue are capable of using L-ergothioneine as an integral component of their antioxidant defense system". Free Radical Biology & Medicine. 46 (8): 1168–76. doi:10.1016/j.freeradbiomed.2009.01.021. PMID 19439218.
  13. ^ Audley BS, Tan CH (1968). "The uptake of ergothioneine from the soil into the latex of Hevea brasiliensis". Phytochemistry. 7 (11): 1999–2000. Bibcode:1968PChem...7.1999A. doi:10.1016/S0031-9422(00)90759-3.
  14. ^ a b c Pluskal T, Ueno M, Yanagida M (2014). "Genetic and metabolomic dissection of the ergothioneine and selenoneine biosynthetic pathway in the fission yeast, S. pombe, and construction of an overproduction system". PLOS ONE. 9 (5) e97774. Bibcode:2014PLoSO...997774P. doi:10.1371/journal.pone.0097774. PMC 4020840. PMID 24828577.
  15. ^ Genghof DS (August 1970). "Biosynthesis of ergothioneine and hercynine by fungi and Actinomycetales". Journal of Bacteriology. 103 (2): 475–8. Bibcode:1970JBact.103..475G. doi:10.1128/JB.103.2.475-478.1970. PMC 248105. PMID 5432011.
  16. ^ Genghof DS, Inamine E, Kovalenko V, Melville DB (November 1956). "Ergothioneine in microorganisms". The Journal of Biological Chemistry. 223 (1): 9–17. doi:10.1016/S0021-9258(18)65113-0. PMID 13376573.
  17. ^ Melville DB, Ludwig ML, Inamine E, Rachele JR (May 1959). "Transmethylation in the biosynthesis of ergothionelne". The Journal of Biological Chemistry. 234 (5): 1195–8. doi:10.1016/S0021-9258(18)98157-3. PMID 13654346.
  18. ^ Seebeck FP (May 2010). "In vitro reconstitution of Mycobacterial ergothioneine biosynthesis". Journal of the American Chemical Society. 132 (19): 6632–3. Bibcode:2010JAChS.132.6632S. doi:10.1021/ja101721e. PMID 20420449.
  19. ^ Bello MH, Barrera-Perez V, Morin D, Epstein L (February 2012). "The Neurospora crassa mutant NcΔEgt-1 identifies an ergothioneine biosynthetic gene and demonstrates that ergothioneine enhances conidial survival and protects against peroxide toxicity during conidial germination". Fungal Genetics and Biology. 49 (2): 160–72. doi:10.1016/j.fgb.2011.12.007. PMID 22209968.
  20. ^ a b Beliaeva, MA; Seebeck, FP (26 September 2022). "Discovery and Characterization of the Metallopterin-Dependent Ergothioneine Synthase from Caldithrix abyssi". JACS Au. 2 (9): 2098–2107. doi:10.1021/jacsau.2c00365. PMC 9516567. PMID 36186560.
  21. ^ Sato, S; Saika, A; Koshiyama, T; Higashiyama, Y; Fukuoka, T; Morita, T (12 April 2025). "Biosynthesis of ergothioneine: current state, achievements, and perspectives". Applied Microbiology and Biotechnology. 109 (1): 93. doi:10.1007/s00253-025-13476-4. PMC 11993508. PMID 40220171.
  22. ^ Yan, J; Chen, Y; Ma, Y; Yang, X; Yao, Y; Zhao, G; Zhang, Y (25 October 2025). "Efficient ergothioneine production through reconstruction of the methyl and sulfur supply systems in Escherichia coli". Trends in Biotechnology. doi:10.1016/j.tibtech.2025.09.014. PMID 41139570.
  23. ^ Hartman PE (1990). "[32] Ergothioneine as antioxidant". Oxygen Radicals in Biological Systems Part B: Oxygen Radicals and Antioxidants. Methods in Enzymology. Vol. 186. pp. 310–8. doi:10.1016/0076-6879(90)86124-E. ISBN 978-0-12-182087-9. PMID 2172707.
  24. ^ Heath H, Toennies G (February 1958). "The preparation and properties of ergothioneine disulphide". The Biochemical Journal. 68 (2): 204–10. doi:10.1042/bj0680204. PMC 1200325. PMID 13522601.
  25. ^ Asmus KD, Bensasson RV, Bernier JL, Houssin R, Land EJ (April 1996). "One-electron oxidation of ergothioneine and analogues investigated by pulse radiolysis: redox reaction involving ergothioneine and vitamin C". The Biochemical Journal. 315 (2): 625–9. doi:10.1042/bj3150625. PMC 1217242. PMID 8615839.
  26. ^ Yamashita Y, Yamashita M (June 2010). "Identification of a novel selenium-containing compound, selenoneine, as the predominant chemical form of organic selenium in the blood of bluefin tuna". The Journal of Biological Chemistry. 285 (24): 18134–8. Bibcode:2010JBiCh.28518134Y. doi:10.1074/jbc.C110.106377. PMC 2881734. PMID 20388714.
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