L-Ergothioneine naturally occurs in living organisms
L-Ergothioneine is incorporated into tissues via a specific transporter
L-Ergothioneine has a slow turnover
In search for the physiological role of L-ergothioneine
Perspectives

 

L-Ergothioneine naturally occurs in living organisms

 

Chemical structure of L-ergothioneine

 

L-Ergothioneine is a natural and water-soluble compound which has been first isolated in rye ergot (Claviceps purpurea) in 1909 by the French pharmacist Charles Tanret [1].

To date, the only organisms known to be able to synthesize L-ergothioneine are bacteria, more specifically mycobacteria [2] and cyanobacteria [3], and fungi of the phyla Ascomycota, Zygomycota and Basidiomycota, which include lower fungi (molds) and higher edible fungi [4-9].

The biosynthesis of L-ergothioneine has been studied in Neurospora crassa [10-12] and mycobacteria [13]. In the first stage, L-histidine is methylated threefold by one specific N-methyltransferase to yield the betaine derivative L-hercynine, with S-adenosyl-methionine as the methylating agent. Sulfur is then added to L-hercynine in an oxidation reaction catalyzed by an iron-containing enzyme. In N. crassa and mycobateria, the reaction uses cysteine or γ-glutamylcysteine, respectively, as the sulfur-donating substrate. Both pathways pass through the formation of hercynyl-cysteine sulfoxide, which is cleaved to yield L-ergothioneine and pyruvate by a β-lyase, in the presence of pyridoxal phosphate.

L-Ergothioneine is found throughout the living world from plants to man, including in particular the well-known horseshoe crab (Limulus polyphemus), one of the oldest living animal species on Earth [14]. However, these organisms are unable to synthesize L-ergothioneine. Plants absorb L-ergothioneine via symbiotic associations between their roots and soil fungi [15,16]. Animals and humans only absorb L-ergothioneine via their respective food chains [3,5,17,18]. In animals, it has been shown that the microbiota does not contribute to the presence of L-ergothioneine in the body [19,20].

The determination of the L-ergothioneine content in common foods shows that edible mushrooms, black and red beans, oat bran, garlic and some meat products (liver and kidney) are the main dietary sources of this compound for man [21,22].

L-Ergothioneine has been identified or assayed in plant tissues [21,23,24] and animal tissues/fluids [14,25-45], including human ones [18,25,27,42,44,46-49].

For a given tissue, high variations are observed in L-ergothioneine concentration, which most probably reflects the lack of specificity and sensitivity of earlier analysis methods and highlights the need to verify these data using more recent analytical techniques such as liquid chromatography coupled to mass spectrometry [50].

L-Ergothioneine is distributed in most tissues, but unevenly, as shown in the mouse: liver > kidney ≃ heart > skin ≃ lung ≃ spleen ≃ small intestine ≃ blood (erythrocytes) > pancreas ≃ testis ≃ muscle ≃ large intestine ≃ brain [42]. Cross-species analysis of its content in organs also reveals differences across species [5,44].

Most often found in the sub-millimolar range, L-ergothioneine may reach millimolar concentrations in some tissues or fluids, for example the lens in man [47], various ocular tissues in cows and pigs [39], and seminal plasma in boars [44].

At subcellular level, it has been shown that L-ergothioneine is mainly distributed in the cytoplasm [28,32]. Use of tritiated L-ergothioneine enabled demonstration that it is also distributed, to a lesser extent, in membranes, mitochondria, nuclei and microsomes [32].

 

L-Ergothioneine is incorporated into tissues via a specific transporter

About a century after the identification of L-ergothioneine, the discovery that it is the physiological substrate of the OCTN1 transporter [51] has boosted the knowledge of this unique natural compound. Earlier characterized in humans and described as a multispecific organic cation transporter [52,53], OCTN1 (also known as SLC22A4) was shown to have a high affinity for L-ergothioneine (Km=21μM) and to be specific for this substrate, whose transport is also sodium dependent (co-transport) [51,54]. ETT, for ergothioneine transporter, was thus proposed as a new name for OCTN1 [51].

In humans, the expression of OCTN1/ETT has been shown in numerous organs, with the highest level in bone marrow, small intestine, trachea, fetal liver, kidney, cerebellum and spinal cord [51,54]. In hematopoietic tissues, OCTN1/ETT is strongly expressed in the erythroid lineage, from the CD71+ (transferrin receptor) progenitor cells until mature erythrocytes [51,55]. In peripheral blood mononuclear cells, OCTN1/ETT is predominantly expressed in CD14+ and is absent in lymphocytes [51,56]. Taken together, these results show that OCTN1/ETT is associated with myeloid cells.

The expression of OCTN1/ETT has been evidenced on the cytoplasmic membrane of various cell types, such as Sertoli cells [57], endothelial cells [58], dermal fibroblasts [59,60], epidermal keratinocytes [60], brain neurons [45], neural progenitor cells [61], and epithelial cells, mainly apically in the latter, as evidenced in renal [62], pulmonary [63,64], ocular [65], small intestinal [66] and nasal [63,67] epithelial cells. In basal epidermal keratinocytes [60] and most probably in glandular cells of seminal vesicles [44], the expression of OCTN1/ETT is basolateral.

OCTN1/ETT expression has also been evidenced at mitochondrial level [68], but this result has been questioned [69].

Metabolomic analysis in OCTN1/ETT gene knock-out mice has shown an almost complete disappearance of L-ergothioneine in the tissues of these mice [42]. This has also been shown in a more in-depth study of the various regions of the brain in the knock-out mice [45] and in the OCTN1/ETT knock-out zebra fish [70]. These studies confirm the key role of the OCTN1/ETT transporter in the tissue absorption of L-ergothioneine. Consistently, the tissue distribution of L-ergothioneine matches the OCTN1/ETT expression pattern and OCTN1/ETT mRNA expression is correlated to L-ergothioneine content [44,45].

OCTN1/ETT expression is regulated by pro-inflammatory cytokines (TNF-α, IL-1β) via the transcription factor NF-κB [71], and it is under the control of RUNX1 [71], whose involvement has been demonstrated in proliferation and differentiation during hematopoiesis [72,73], neurogenesis [74], and hair morphogenesis [75].

It should be noted that OCTN1/ETT knockdown studies support a role of this transporter and L-ergothioneine (see below) in cell proliferation and differentiation, as shown in erythroid cells [76] and neuronal cells [45,61].

OCTN1/ETT-gene variants have been associated with chronic inflammatory diseases in specific populations, e.g. the slc2F2 variant with rheumatoid arthritis [56,77] and the L503F variant with Crohn's disease [78,79], the latter being in particular associated with a slightly more efficient L-ergothioneine transport [80]. The involvement of these variants as causal genes for these diseases has not been demonstrated and is even questioned for the L503F variant [81]. Indeed, it has been suggested that the increase of L503F variant frequency is the result of genetic hitchhiking [82]. Interestingly, the authors of this study suggest that it would also be an adaptation to low dietary levels of L-ergothioneine among early Neolithic farmers in the Fertile Crescent [82].

In this context, it is interesting to note that OCTN1/ETT knock-out mice show lower tolerance to intestinal oxidative stress [42].

 

L-Ergothioneine has a slow tissue turnover

The kinetics of incorporation and tissue elimination of L-ergothioneine were studied in rodents, following oral absorption of L-ergothioneine [42,83-85] or after intraperitoneal or intravenous injection [35]. These studies show that L-ergothioneine has a slow turnover. It accumulates gradually and at different speeds in the organs and in blood, and it is also strongly retained in tissues.

A relatively early study in rats showed the effect of age and gender on the blood concentration of L-ergothioneine [84]. In that study, the authors show that, in rats maintained on a normal diet, the blood concentration of L-ergothioneine doubles during the first 3 months of life for both sexes. But while this concentration is stabilized up to 18 months (end of study) in the female, it reaches a plateau at a value twice as high in male rats. These authors have also shown that testosterone may be the cause of this increased accumulation in the male. No other study on the effect of gender on the tissue concentration of L-ergothioneine has been reported to date.

The effect of age on erythrocyte concentration of L-ergothioneine was also identified in a population of men with an increase in concentration between the age of 1 and 10 years, which peaks at about 18 and decreases until about 50, when it stabilizes [48].

In rats, L-ergothioneine has been shown to pass from the mother to the neonate or pup during weaning via maternal milk [86]. This finding is consistent with the evidencing of the OCTN1/ETT transporter in the mammary epithelium [87,88].

In the current state of knowledge, no metabolite of L-ergothioneine has been identified so far in man or animals.

 

In search for the physiological role of L-ergothioneine

The following intrinsic properties of L-ergothioneine have been shown in vitro:

  • Sequestering, reducing or disactivating highly oxidizing chemical entities: hypochlorous acid [89], peroxynitrite anion [90], peroxyl radicals [91], ferrylmyoglobin [92], singlet oxygen [93,94], and photosensitizer in the excitated state [95].
  • Chelating metal cations (copper, mercury, cadmium, zinc) [96-98] and, in particular, preventing the pro-oxidative effects of copper [99-101].

In a biological context, numerous studies have evidenced antioxidant activities and/or protective effects of L-ergothioneine under experimental conditions involving oxidative stress, i.e. following stimulation by pro-inflammatory or pro-oxidizing agents/conditions.

Such in vitro properties of L-ergothioneine are summarized below:

  • Protection of bacteriophages T4 and P22 against γ-irradiation-induced inactivation [102].
  • Protection of isolated rat heart from ischemia/reperfusion-induced injury [92].
  • Protection against macromolecule damage and/or cell death induced by reactive oxygen species in HeLa [103] and PC12 [104] cells, by peroxynitrite anion in N-18-RE 105 cells [105], by UV [60] and UVA/visible light [106] radiations in human epidermal keratinocytes, by UVA in human dermal fibroblasts [107], and by cisplatin [108] and β-amyloid peptide [109] in PC12 cells.
  • Inhibition of UVB-induced up-regulation of TNF-α expression [110], and UVA-induced MMP-1 [110] and peroxide [59] production in human dermal fibroblasts.
  • Inhibition of hydrogen peroxide-induced apoptosis and p38 MAPK phosphorylation in PC12 cells [104].
  • Inhibition of β-amyloid peptide-induced apoptosis, caspase-3 activity and PARP cleavage in PC12 cells [109].
  • Inhibition of UV-induced apoptosis, caspase-9 expression and PARP-1 activation in human epidermal keratinocytes [60].
  • Inhibition of hydrogen peroxide- and TNF-α-induced NF-κB activation and IL-8 release in epithelial cells [111].
  • Inhibition of IL-1β-induced endothelial expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin), and subsequent monocyte binding [112].
  • Inhibition of IL-6 production by C2C12 myoblasts [113] and 3T3-L1 adipocytes [114] following stimulation by palmitic acid and TNF-α, respectively.
  • Inhibition of mushroom polyphenoloxidase activity [115].

Furthermore, in OCTN1/ETT knockdown HeLa cells, L-ergothioneine depletion resulted in a higher susceptibility to oxidative stress [103].

Consistently with such in vitro antioxidant properties, L-ergothioneine has been shown to improve food preservation by preventing discoloration and lipid peroxidation of meat [115,116].

In neural progenitor cells, a recent study has demonstrated that L-ergothioneine inhibits cell proliferation and promotes neuronal differentiation, in correlation to inhibition of the intracellular production of reactive oxygen species and up-regulation of Math1 gene, respectively [61].

With respect to reproduction, the following effects of L-ergothioneine have been described:

  • Decrease of the inhibitory effect of p-chloromercuribenzoic acid on spermatozoa respiration in the guinea pig [117].
  • Increase in the acrosome reaction of guinea pig spermatozoa, and increase in the fertility of mouse spermatozoa, both in vitro and in vivo in the latter case [118].
  • Increase in the oocyte maturation and embryonic development in the ewe [119].
  • Increase in spermatozoa preservation in the guinea pig [117], stallion [120] and ram [121-123].

It should be noted that the L-ergothioneine protection against deleterious effects of reactive oxygen/nitrogen species and ischemia/reperfusion-induced injury in isolated rat heart were not confirmed by other groups, references [21] and [124], respectively, owing to differing experimental conditions and/or concentrations used.

In vivo protective effects of L-ergothioneine are summarized below:

  • Protection of N. crassa conidia against peroxide damage during germination, and improvement of their longevity [12].
  • Decrease of nitrite-induced methemoglobin formation in rabbits [125] and rats [126].
  • Prevention of the teratogenic effects of cadmium in mice [127].
  • Protection against ethionine-induced liver injury in rats [128].
  • Decrease of the rate of embryo malformation in diabetic rats [129].
  • Protection against ischemia/reperfusion-induced injury in rat liver [130] and small intestine [131].
  • Protection against oxidative damage induced by ferric-nitrilotriacetate in rat liver and kidney [132].
  • Neuroprotection against NMDA excitotoxicity in rats [133], and cisplatin [108] and β-amyloid [134] toxicity in mice.
  • Protection against cytokine-induced inflammation and injury in rat lungs [135].

Through these in vivo studies, it was in particular shown that L-ergothioneine treatment, with respect to no treatment, resulted in decreasing lipid peroxidation and saving endogenous antioxidant defenses, such as vitamin E and glutathione.

No clinical data have been published to date regarding the effect of specifically administering pure Lergothioneine in humans.

 

Perspectives

Despite numerous studies, the in vivo role of L-ergothioneine remains unknown today. It has been suggested that L-ergothioneine may represent a new vitamin [103], but its essential role has not been discovered yet through deprivation or knockout in vivo studies, the resulting animals being phenotypically similar to control animals. Such an essential role might be only displayed under stress conditions and/or after a longer period of observation.

Given its tissue absorption by a specific transporter and its in vivo protective effects, L-ergothioneine can at least be considered as a physiological antioxidant endowed with anti-inflammatory properties.

However, naming L-ergothioneine an "antioxidant" might be confusing if this property is only related to its ability to scavenge reactive oxygen/nitrogen species. Indeed, chemically speaking, L-ergothioneine is a weak reducing agent at physiological pH, due to the fact that its thione tautomeric form predominates at these pH [136]. This accounts in particular for its stability towards oxygen in aqueous solution, which distinguishes it from other biological thiols such as glutathione and dihydrolipoic acid.

In a biological context, another antioxidant mechanism may account for the protective effects of L-ergothioneine. It is related to the ability of L-ergothioneine to specifically interact with proteins, as it was shown in the case of its transporter. This putative mechanism remains to be investigated in regard to redox alterations of protein cysteine residues, such as disulfide formation, nitrosylation and metal coordination. It is now well established that these reversible chemical modifications play a key role in the redox signaling of cellular events and cell fate. So in that case, defining L-ergothioneine as a modulator of redox homeostasis would be more appropriate to describe its antioxidant mechanism of action.

Tissue absorption of L-ergothioneine by a specific transporter implies a beneficial role of this unique micronutrient, which has also been shown to be not mutagenic, nor genotoxic [137,138], and well tolerated in investigations of various health indications [139-141]. A better understanding of its role requires more studies and deserves further attention with regard to human health, in particular as micronutrient deficiencies may increase the risk of developing age-related disorders and diseases [142-144]. Their development is correlated with a mild pro-inflammatory state in which oxidative stress, i.e. disruption of redox signaling and control [145], plays a major role.

This has led Tetrahedron to develop a novel industrial process (WO2011042480), using a biomimetic and sustainable approach [146], to make L-ergothioneine available and to supply it in bulk quantities. Tetrahedron supplies L-ergothioneine for Research and can propose a GMP quality product whose characterization and safety have been assessed according to regulatory requirements for its use as a nutritional ingredient in humans.

For more information on our product, please contact us.

 

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