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Herein, we explore six short polyphenol oxidases (PPOs) from lignocellulose\u2010degrading ascomycetes for their capacity to react with G\u2010type and S\u2010type phenolic compounds. All six PPOs catalyze the <jats:italic>ortho\u2010<\/jats:italic>hydroxylation of G\u2010type compounds (guaiacol, vanillic acid, and ferulic acid), forming the corresponding methoxy\u2010<jats:italic>ortho<\/jats:italic>\u2010diphenols. Remarkably, a subset of these PPOs is also active towards S\u2010compounds (syringol, syringic acid, and sinapic acid) resulting in identical methoxy\u2010<jats:italic>ortho\u2010<\/jats:italic>diphenols. Assays with <jats:sup>18<\/jats:sup>O<jats:sub>2<\/jats:sub> demonstrate that these PPOs in particular catalyze <jats:italic>ortho<\/jats:italic>\u2010hydroxylation and <jats:italic>ortho<\/jats:italic>\u2010demethoxylation of S\u2010compounds and generate methanol as a co\u2010product. Oxidative (<jats:italic>ortho<\/jats:italic>\u2212) demethoxylation of S\u2010compounds is a novel reaction for PPOs, which we propose occurs by a distinct reaction mechanism as compared to aryl\u2010O\u2010demethylases. We further show that addition of a reducing agent can steer the PPO reaction to form methoxy\u2010<jats:italic>ortho<\/jats:italic>\u2010diphenols from both G\u2010 and S\u2010type substrates rather than reactive quinones that lead to unfavorable polymerization. Application of PPOs opens for new routes to reduce the heterogeneity and methoxylation degree of mixtures of G and S lignin\u2010derived compounds.<\/jats:p>","DOI":"10.1002\/anie.202409324","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T19:18:25Z","timestamp":1726600705000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Polyphenol Oxidase Activity on Guaiacyl and Syringyl Lignin Units"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6838-2939","authenticated-orcid":false,"given":"Caio","family":"de O. G. Silva","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Biomedicine Technical University of Denmark  S\u00f8ltofts Plads, Building 221, Kgs. 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Lyngby 2800 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7796-3089","authenticated-orcid":false,"given":"Jane W.","family":"Agger","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biomedicine Technical University of Denmark  S\u00f8ltofts Plads, Building 221, Kgs. Lyngby 2800 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl3419"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6GC01531J"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj0053"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-022-12007-9"},{"key":"e_1_2_7_5_1","volume":"63","author":"Wu X.","year":"2024","journal-title":"Angew. Chem. Int. 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