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In <jats:italic>Vreelandella boliviensis<\/jats:italic> and other halophilic bacteria, genes encoding the guanidine carboxylase pathway are found in a guanidine riboswitch-regulated operon, along with two uncharacterized genes annotated as 2-oxoglutarate (2-OG\/Fe(II))-dependent dioxygenase family protein and hypothetical protein, respectively. Here we show that the 2-OG\/Fe(II)-dependent dioxygenase efficiently hydroxylates methylguanidine. The resulting N-(hydroxymethyl)guanidine constitutes an unexpectedly stable hemiaminal that slowly decays to guanidine and formaldehyde. The second protein strongly accelerates the fragmentation of N-(hydroxymethyl)guanidine into guanidine and formaldehyde, thus acting as N-(hydroxymethyl)guanidine lyase. Interestingly, the class II guanidine riboswitch in front of the guanidine carboxylase gene does not discriminate between guanidine and methylguanidine, whereas the guanidine class I riboswitch at the start of the entire operon is specific for guanidine. <jats:italic>V. boliviensis<\/jats:italic> exhibits growth in minimal media with either guanidine or methylguanidine as sole nitrogen source. Comparative proteome analysis revealed that the entire guanidine carboxylase operon is strongly expressed under these conditions. The presented study broadens our understanding of guanidine metabolism by describing two enzymatic activities that jointly catalyze the demethylation of methylguanidine.<\/jats:p>","DOI":"10.1038\/s41467-025-64776-2","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:05:34Z","timestamp":1759917934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Demethylation of methylguanidine by a stepwise dioxygenase and lyase reaction"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-9686","authenticated-orcid":false,"given":"Malte","family":"Sinn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9855-0419","authenticated-orcid":false,"given":"Dietmar","family":"Funck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0235-4905","authenticated-orcid":false,"given":"Felix","family":"Gamer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Blumenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Kramp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6601-7217","authenticated-orcid":false,"given":"J\u00f6rg S.","family":"Hartig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"64776_CR1","doi-asserted-by":"publisher","first-page":"12889","DOI":"10.1093\/nar\/gkaa1102","volume":"48","author":"F Lenkeit","year":"2020","unstructured":"Lenkeit, F., Eckert, I., Hartig, J. 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