L-ergothioneine: from its physiological role to its physiological effect

Halliwell et al. published recently an excellent and complete review on L-ergothioneine (Halliwell, B. Cheah, I. and Tang, R.; 2018).
L-ergothioneine cannot be synthesized by humans and therefore is available only from dietary sources.
The normal presence of L-ergothioneine in almost all the tissues, including brain, skin, eyes, lungs, liver, heart, kidneys and reproductive organs, suggests its potential importance for the maintenance of good health as well as its potential both for treating and/or preventing a variety of disorders.
Up to now its physiological role is not totally clarified. The avidity by which dietary L-ergothioneine is incorporated into tissues, the tenacity with which it is retained in the body and its unique non-uniform pattern in large tissue distribution serve to support the physiological importance of this fascinating molecule.

From the physiological role of ergothioneine …

… as a weak direct antioxidant

As any other molecule ergothioneine can act as  direct antioxidant with respect to any other compound having a redox potential higher than those of ergothioneine. A lot of in vitro studies contributed to evidence « this intrinsic property ». Meanwhile based only on the redox potential values ergothioneine is a poorer direct antioxidant than several direct/secondary antioxidants such as glutathione, lipoic acid, vitamin C, vitamin E or polyphenols for example.
« Ergothioneine is a weak antioxidant in comparison with other compounds in the cell (glutathione, thioredoxin or lipoïc acid for example), which isn’t necessarily a bad thing.» (B. Ames, 2014).

Two major reasons to explain this:

  1. firstly because «specificity is the key» (B. Ames, 2014)
    Life being not possible without regulation/control Nature developped several levels of control. One of them concerns the intake of nutriments into our cells through specific transporters. Ergothioneine owns a specific transporter called OCTN1 or ETT.
    Any time you can target a tissue and deliver a nutrient specifically to that tissue, the effects will be greater than using a nutrient that distributes all over the body — even if that nutrient is stronger than the more specific one.
    « The presence of a specific transporter suggests that animals (including humans) may gain benefit from obtaining ergothioneine and retaining it in their tissues. It is an interesting contrast to polyphenols, also powerful antioxidants in vitro, which are rapidly metabolized and excreted from the body, suggesting that they are not required by animals and thus promptly disposed of. As another example, four tocopherols and four tocotrienols from the diet can exert antioxidant effects but only RRR-a-tocopherol is retained by the body; the others are discarded, implying they are less useful. Like ergothioneine, vitamin C, an essential diet-derived enzyme co-factor and possible in vivo antioxidant, also has selective transporters for intestinal uptake and delivery to tissues.” (B. Halliwell, 2016)
  2. secondly because « more the compound is antioxidant more quickly it is oxidized » and moreover the oxidized form is always more or less toxic for the cell. » (B. Ames, 2014)

Is it better to get a powerful antioxidant such as polyphenols for example whose bioavailability is not controlled and moreover which can be toxic at the active dose for our cells or to get a poorer antioxidant whose the bioavailability is under control of a specific transporter and which owns no toxicity at the physiological dose ?

However, naming L-ergothioneine an  » direct 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, likely due to the fact that its thione tautomeric form predominates at these pH. 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.

… as modulator of the Redox Homeostasis

In a biological context, another protection mechanism against oxidative stress damage may account for the cytoprotective effects of L-ergothioneine. This mechanism doesn’t involve its direct antioxidant capacities but is related to the ability of L-ergothioneine to specifically interact with proteins. That’s why it is called indirect antioxidant mechanism.

The first example described is its transport inside the cell via its specific transportet OCTN1/ETT (Gründemann, 2005). More recently it has been described for the first time that L-ergothioneine is used as co-factor in the case of a bacterial enzyme (Zhao, 2015).

More recently L-ergothioneine has been evidenced as a activator of the master transcription factor Nrf2 at nanomolar scale in human keratinocytes (Hseu, 2016). Nrf2 is the master regulator for all genes coding for antioxidant enzymes forming the Anitoxidant System of the cells.  Unlike most known activators of Nrf2 which are electrophiles L-ergothioneine is nucleophile and then should have a specific mode of action. It remain to be determined whether L-ergothioneine acts directly or indirectly to modulate Nrf2. This putative indirect 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 through its activation effect of Nrf2, defining L-ergothioneine as a modulator of redox homeostasis would be more appropriate to describe its antioxidant mechanism of action.

 

… to the physiological effect of ergothioneine

from the cell protection effect…

Thanks to the ergothioneine transporter (OCTN1/ETT), L-ergothioneine gets delivered all over the body and particularly where most needed. Based on many scientific studies one role clearly elucidated for L-ergothioneine is that of a physiological molecule protecting our cells and tissues against oxidative stress – similar to vitamins C and E – as summarized in the following scheme (Cheah; 2012).

« The description of a highly specific L-ergothioneine transporter (OCTN1/ETT) further underscores its potential importance as « an important physiological cytoprotective agent which probably merits designation as a « possible vitamin » (Paul & Snyder; 2010).

… to the modulation of inflammation

  1. through the activation of the cell defence effect against pathogens
  2. and the inhibition of low-level inflammation via the inhibition of the pro-inflammatory transcription factors (NfκB, …)
  3. inhibition of the pro-inflammatory cytokines (IL8, …)
  4. inhibition of the adhesion molecules (E-Cam et V-CAM, …)

L-ergothioneine owns numerous properties that may be beneficial in maintaining overall health and reducing the risk and progression of disorders associated with overt as well as silent/low-level inflammation.

Very recently, L-ergothioneine has been considered as a « putative longevity vitamin » (Ames, PNAS 2018).

In summary, L-ergothioneine can be considered as unique natural cell-protective micronutrient (Halliwell & Gutteridge; 2015) for humans and animals.