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While amino acid substitutions in mutant SOD1 destabilize its structure and promote misfolding, oxidation has also been implicated in the pathological alterations of wild\u2010type SOD1, particularly in neurodegenerative diseases including sporadic ALS. However, the impact of oxidation on SOD1 folding remains to be fully elucidated. Here, we demonstrate that Cys111 is primarily oxidized to sulfonic acid upon exposure of apo\u2010SOD1 to hydrogen peroxide, as confirmed by the quantitation of thiol groups and mass spectrometry. Molecular dynamics simulations showed that sulfonylation of Cys111 disrupts the dimer interface and promotes monomerization. This monomeric form then facilitates the subsequent oxidation of buried Cys6, leading to structural disruption, as evidenced by circular dichroism spectroscopy and loss of thiol groups. SOD1 denaturation triggered by Cys111 oxidation became evident when zinc binding was impaired due to pathological mutations and\/or under zinc\u2010deficient conditions. Given that increased oxidative stress is frequently associated with many neurodegenerative diseases, modulating Cys111 oxidation may offer a potential strategy for maintaining SOD1 structural stability and preventing its pathological misfolding.<\/jats:p>","DOI":"10.1002\/pro.70339","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:59:29Z","timestamp":1760623169000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oxidative denaturation of Cu\/Zn\u2010superoxide dismutase associated with neurodegenerative diseases"],"prefix":"10.1002","volume":"34","author":[{"given":"Moeno","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Chemistry Keio University  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norifumi","family":"Muraki","sequence":"additional","affiliation":[{"name":"Department of Chemistry Keio University  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