Abstract: Abstract Ergothioneine (ESH) is one of the most abundant antioxidants in the human body, but its biological functions remain unclear. In this work, we elucidated the detailed mechanism of the deactivation of divalent copper ions Cu(II) by ESH using optical spectroscopy, NMR, and LC-MS. We found that the reduction of Cu(II) ions to Cu(I) by ESH occurs in a bimolecular reaction of CuII(ES−)2 complexes, leading to the formation of the disulfide ESSE. Cu(I) ions remain bound in stable complexes with ESH, preventing their reactions with molecular oxygen. Over longer timescales, ESSE decomposes, regenerating reduced ESH and forming the final reaction product, hercynine (EH). The conversion of one ESH molecule to EH causes the reduction of four Cu(II) ions. We determined the rate constants of the bimolecular reaction between CuII(ES−)2 complexes to be k3 = (8 ± 4) × 104 M−1s−1 and of ESSE hydrolysis to be k4 = (1.7 ± 0.4) × 10−5 s−1 and also estimated the formation constant K12 ≈ 1.2 × 1017 M−2 for the CuII(ES−)2 complex. The high efficiency of Cu(II) reduction and the chelation of the resulting Cu(I) ions in a stable complex supports the hypothesis that protecting cells from oxidation by metal ions is likely one of the main functions of ESH.

Cite: Tsentalovich Y.P. , Osik N.A. , Fomenko M.V. , Dmitriev N.A. , Yanshole V.V.
Mechanism of Cu(II) Detoxification by Ergothioneine: Reduction and Formation of Stable Cu(I) Complexes
Antioxidants. 2026. V.15. N9. 1064 :1-19. DOI: 10.3390/antiox15091064 OpenAlex

Dates:

Submitted:	Jul 21, 2026
Accepted:	Aug 21, 2026
Published print:	Aug 25, 2026

Identifiers:

≡ OpenAlex:

W7204185448

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