Ergothioneine, where are we now?

The water-soluble thione/thiol ergothioneine (ET) was first isolated in 1909 by Charles Tanret [1], from the ergot fungus Claviceps purpurea. This fungus is notorious for the toxicity of some of its metabolites to humans, causing ergotism [2], which has even been linked to the Salem witch trials [3]. However, ergotism has nothing to do with ET, which is instead very safe for human consumption and is synthesized by a range of other fungi and some bacteria (reviewed in [4–9]). Its biosynthetic pathways are reviewed in detail in [6]. Indeed, as far as we know, humans and other animals obtain all their ET from the diet [4,5,7–10], whereas plants seem to obtain it from fungi and other soil microorganisms [9]. An enormous amount of work was done on ET in the 1950s, as summarized in the excellent review by Melville [7]. Interest then waned but has picked up rapidly in recent years (Fig. 1). We, therefore, thought that it was about time for a collection of articles and reviews highlighting the recent developments in the ET field. We, thus, approached both FEBS Letters, which was very supportive, and a range of experts working on ET, who were almost uniformly enthusiastic and happy to contribute. The FEBS Letters Special Issue ‘Ergothioneine, where are we now?’ is the result of these activities and contains 11 articles by leading experts. One catalyst for this upsurge of interest was the discovery in 2005 of a transporter for ET (OCTN1, often now called the ergothioneine transporter, ETT), which accounts for the fact that animals (including humans) take up and avidly retain ET from the diet [11]. The specificity of ETT for ET has often been challenged but has been reconfirmed in several studies [11–13], as reviewed in depth by Grundemann et al. in this special issue [14]. The presence of a specific transporter together with the avid retention of ET in the body implies that this compound is important to us, and indeed in 2018 Bruce Ames proposed that ET be classified as a ‘longevity vitamin’ [15]. No specific deficiency disease has yet been identified for ET, which makes it hard to formally classify it as a vitamin. Perhaps, however, deficiency diseases are staring us in the face: low blood or plasma levels of ET are correlated with increased risk of frailty [16–18], cardiovascular disease [19], mild cognitive impairment [18, 20–22], dementia [22,23] and Parkinson’s disease [24]. Indeed, ET has many neuroprotective properties [4,5,18,26,27], as reviewed in detail in this special issue [18,25,26]. Consistent with a key protective role of ET against the development of age-related diseases, higher dietary consumption of mushrooms, a rich source of ET [9], is associated with lower disease risk [28–31]. However, we must be cautious; to quote an old phrase ‘correlation does not imply causation’. Low ET levels may predispose to disease, but disease could also lead to low ET levels. Possible reasons could include alterations in diet due to illness so that less ET is consumed, and/or decreases in ETT activity in the gut (leading to less ET uptake) or kidney (impairing ET