Ergothioneine Biosynthesis and Antioxidant Mechanisms

Ergothioneine is a histidine-derived thiol compound synthesised by bacteria and fungi through a dedicated multistep pathway. Initial methylation of histidine yields hercynine, which undergoes enzymatic oxidative sulphur transfer via a non-heme iron-dependent enzyme, followed by C–S lyase activity to form the final thione. Animals and plants lack this biosynthetic capacity and rely on dietary uptake mediated by the high-affinity transporter SLC22A4. Once internalised, ergothioneine accumulates in tissues prone to oxidative stress and exerts cytoprotective effects through radical scavenging, metal chelation and modulation of redox homeostasis without perturbing endogenous thiol balances. Emerging evidence highlights its role as an auxiliary antioxidant, potentially qualifying it as a conditionally essential micronutrient.

Research from Nature Portfolio

Recent studies have mapped the uptake and tissue distribution of dietary ergothioneine in murine models, revealing selective enrichment in liver, blood, kidney, heart, lung and brain. High‐resolution mass spectrometry characterised associated metabolites—hercynine, S-methyl ergothioneine and ergothioneine sulfonate—suggesting tissue-specific defence mechanisms against oxidative insults. Concurrently, metabolic engineering of Escherichia coli has achieved gram-scale fermentative production by overexpressing the complete egtBCDE operon and reinforcing cysteine and histidine precursor pathways. Strategic gene disruptions to derepress methionine metabolism and optimised fed-batch fermentation protocols now yield titres exceeding 1 g L–1, demonstrating a scalable route for nutraceutical manufacture.

Ergothioneine Biosynthesis and Antioxidant Mechanisms publication trend

The graph below shows the total number of articles in ergothioneine biosynthesis and antioxidant mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

SLC22A4: A high-affinity organic cation transporter responsible for cellular uptake of ergothioneine.

Hercynine: Nα,Nα,Nα-Trimethylhistidine, the methylated precursor in the ergothioneine biosynthetic pathway.

Non-heme iron enzyme: A metalloenzyme family catalysing oxidative sulphur transfer during ergothioneine formation without haem prosthetic groups.

Fed-batch fermentation: A bioprocess in which nutrients are incrementally supplied to sustain cell growth and maximise product synthesis.

References

1. Diet-Derived Antioxidants: The Special Case of Ergothioneine. Annual Review of Food Science and Technology (2023).
2. Ergothioneine and its congeners: anti-ageing mechanisms and pharmacophore biosynthesis. Protein & Cell (2023).
3. The biology of ergothioneine, an antioxidant nutraceutical. Nutrition Research Reviews (2020).
4. Distribution and accumulation of dietary ergothioneine and its metabolites in mouse tissues. Scientific Reports (2018).
5. Gram-scale fermentative production of ergothioneine driven by overproduction of cysteine in Escherichia coli. Scientific Reports (2019).
6. Engineering the Yeast Saccharomyces cerevisiae for the Production of L-(+)-Ergothioneine. Frontiers in Bioengineering and Biotechnology (2019).
7. Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate. Scientific Reports (2015).
8. Molecular and Functional Characterization of Organic Cation/Carnitine Transporter Family in Mice*. Journal of Biological Chemistry (2000).