L-(+)-Ergothioneine


ergot

Synonyms: Thioneine, thiolhistidine betaine, 2-mercaptohistidine trimethylbetaine

L-Ergothioneine is a natural and water-soluble compound which has been first isolated from Claviceps purpurea in 1909 [1]. It is almost ubiquitous in living organisms and it has been found in particular in the well-known horseshoe crab (Limulus polyphemus), one of the oldest living animal on Earth [2].

L-Ergothioneine has been shown to be biosynthesized in fungi (such as Neurospora crassa) and mycobacteria [3-5]. Incorporated into plants, it is ingested by animals and humans through their diet. The determination of the 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 [6,7].

L-Ergothioneine is distributed in most human and animal tissues where it can reach sub-millimolar or even millimolar concentrations. It has been found in particular in liver, kidney, heart, skin, lung, spleen, small intestine and blood (in erythrocytes) [8], as well as in ocular tissues [9] and seminal plasma [10-12].

L-Ergothioneine is absorbed in tissues through a specific organic cation transporter, OCTN1 (or ETT), which has been identified as such in 2005 [13]. This discovery, about a century after that of L-ergothioneine, has boosted the advancement of knowledge of this fascinating natural compound. Earlier characterized in humans [14], OCTN1 was shown to have a high affinity for L-ergothioneine (Km=21μM, i.e., 100 times more than that of L-carnitine) involving a Na +-dependent anti-transport [13,15]. Expressed on the cytoplasmic membrane, OCTN1 localization has also been shown in mitochondria [16].

Metabolomic analysis in Octn1 gene knockout mice showed an almost complete disappearance of L-ergothioneine in tissues of these mice [8].

The profile of OCTN1 expression corroborates the ergothioneine distribution [13-15,17-22]. It is characterized by a high expression in the bone marrow, and more precisely in CD14+ monocytes and CD71+ (transferrin receptor) erythroid progenitor cells [13]. OCTN1 is not expressed on erythrocytes, which incorporate L-ergothioneine during erythropoiesis [23].
OCTN1 expression is regulated by pro-inflammatory cytokines (TNF-α, IL-1β) via the transcription factor NF-κB [24], and it is under the control of RUNX1 [24], whose involvement has been demonstrated in proliferation and differentiation during hematopoiesis [25,26], neurogenesis [27] and hair morphogenesis [28].

Finally, it has been shown that OCTN1 knockdown results in:

  • A decrease of differentiation and L-ergothioneine uptake in K562 cells (cells from human chronic myelogenous leukemia) [29]
  • An increase of oxidative stress-induced alterations in HeLa cells (human epithelial cell line) [30]

Numerous antioxidant and potential pharmacological properties have been demonstrated for L-ergothioneine:

in vitro

  • Trapping of strong oxidizing species: HOCl [31], ONOO- [32], ROO• [33]
  • Quenching of singlet oxygen (1O2) [34,35] and excited photosensitizer [36]
  • Chelation of divalent metallic cations (Cu2+, Zn2+ [37,38]) and prevention of pro-oxidant effects of copper [39]
  • Reduction of Fe(IV)-Hb/Mb and protection of isolated rat heart from ischemia/reperfusion-induced injury [40]
  • Protection of cellular macromolecules from damage induced by oxidative stress [30,41]
  • Inhibition of hydrogen peroxide- and TNF-α-induced NF-κB activation and IL-8 release in epithelial cells [42]
  • Inhibition of IL-1β-induced endothelial expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and subsequent monocyte binding [43]
  • Inhibition of PC12 apoptosis induced by hydrogen peroxide [44] / β-amyloid peptide [45]
  • Inhibition of palmitic acid-induced IL-6 production by C2C12 myoblasts [46]
  • Stimulation of Caco-2 cells proliferation [47]

in vivo

  • Decrease of nitrite-induced methemoglobin formation in rabbits [48,49]
  • Neuroprotection against NMDA excitotoxicity in rats [50]
  • Decrease of the rate of embryo malformation in diabetic rats [51]
  • Protection against ischemia/reperfusion-induced injury: rat liver [52] and small intestine [53]
  • Protection against oxidative damage induced by ferric-nitrilotriacetate in rats [54]
  • Neuroprotection against cisplatin toxicity in mice [55]

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 [30], 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 revealed under stress conditions.

L-Ergothioneine can at least be considered as a physiological antioxidant endowed with anti-inflammatory properties. Naming this compound solely an "antioxidant" might be confusing if this property is only related to its ability to trap reactive oxygen/nitrogen species. Indeed, in vivo, the ability of L-ergothioneine, to also specifically interact with macromolecules (other than its transporter) remains to be addressed, in particular towards redox alterations of proteins, such as disulfide formation, nitrosylation and metal coordination. These chemical modifications are known to 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.

L-Ergothioneine is used as an active ingredient in Cosmetics, in topical application. This development is strongly supported by the fact that L-ergothioneine naturally occurs in skin and is able to counterbalance the effect of key mediators involved in skin aging, and in particular in skin photodamage. The photoprotective effect of L-ergothioneine has been demonstrated in vitro [20,21,56,57]. Developing oral applications of L-ergothioneine to face skin aging could also be an interesting strategy.

A dietary supplement containing synthetic L-ergothioneine, ERGOFLEX, has recently been launched by Oxis International Inc. in US. This product is intended to relieve joint pain.

The unique antioxidant and anti-inflammatory properties of L-ergothioneine (while being stable towards O2) and its safe toxicity profile support further development in nutrition, as well as in therapeutical or biomedical applications. This has led us to develop a novel industrial process (Application WO2011042480), using a biomimetic and sustainable approach, to supply L-ergothioneine in bulk quantities.


References

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