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Two cancer-linked human Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, the fat mass and obesity\u00a0associated-protein (FTO), and AlkB human homolog 5 (ALKBH5) catalyse m6A methyl group oxidation. While ALKBH5 has consistently been reported to catalyse m6A demethylation, there are conflicting reports concerning the FTO products. We report studies using mass spectrometry and nuclear magnetic resonance comparing products of FTO, ALKBH5, and DNA damage repair demethylases (human ALKBH2 and ALKBH3 and bacterial AlkB, using m1A single-stranded DNA substrates). The results with m6A-containing single-stranded RNA (ssRNA) and N6,2\u2032-O-dimethyladenosine\u00a0adjacent to the 5\u2032 m7G triphosphate cap ssRNA substrates imply that\u00a0the predominant FTO product is N6-hydroxymethyladenosine, either with or without methylation on the substrate ribose 2\u2032-hydroxyl group. The nascent hemiaminal product undergoes relatively slow non-enzyme catalysed fragmentation giving adenosine\/formaldehyde. The other four 2OG-dependent oxygenases tested, including ALKBH5, produce demethylated bases as the predominant products. The results imply that, at least in isolated form, FTO preferentially acts as a hydroxylase, producing a hemiaminal product, rather than a demethylase, distinguishing it from ALKBH5. They highlight a need for investigations into the roles of hemiaminal-type modifications to nucleic acids, in both\u00a0healthy biology and disease.<\/jats:p>","DOI":"10.1093\/nar\/gkaf813","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T10:41:53Z","timestamp":1756377713000},"source":"Crossref","is-referenced-by-count":7,"title":["Evidence human FTO catalyses hydroxylation of <i>N<\/i>6-methyladenosine without direct formation of a demethylated product contrasting with ALKBH5\/2\/3 and bacterial AlkB"],"prefix":"10.1093","volume":"53","author":[{"given":"Simranjeet","family":"Kaur","sequence":"first","affiliation":[{"name":"Hong Kong Baptist University Department of Chemistry, , Kowloon Tong , Hong Kong SAR ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratheesh","family":"Maheswaran","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqi","family":"Lai","sequence":"additional","affiliation":[{"name":"Hong Kong Baptist University Department of Chemistry, , Kowloon Tong , Hong Kong SAR ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eidarus","family":"Salah","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifali","family":"Shishodia","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Schofield","sequence":"additional","affiliation":[{"name":"Chemistry Research Laboratory, University of Oxford The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, , 12 Mansfield Road , Oxford OX1 3TA ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-173X","authenticated-orcid":false,"given":"Wei Shen","family":"Aik","sequence":"additional","affiliation":[{"name":"Hong Kong Baptist University Department of Chemistry, , Kowloon Tong , Hong Kong SAR ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"2025082806414617300_B1","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.cell.2017.05.045","article-title":"Dynamic RNA modifications in gene expression regulation","volume":"169","author":"Roundtree","year":"2017","journal-title":"Cell"},{"key":"2025082806414617300_B2","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.molcel.2019.04.025","article-title":"Where, when, and how: 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