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They are Fe(II)\u2010dependent dioxygenases with a cupin fold that supports a 3xHis metal\u2010coordinating triad at the active site. They also have other, broadly common features including arginine residues involved in substrate carboxylate binding and a conserved trio of residues at the active site featuring a tyrosine important in substrate binding catalysis. Recently, N\u2010terminal cysteinyl dioxygenase enzymes (NCOs) have been identified in plants (plant cysteine oxidases, PCOs), while human 2\u2010aminoethanethiol dioxygenase (ADO) has been shown to act as both an NCO and a small molecule TDO. Although the cupin fold and 3xHis Fe(II)\u2010binding triad seen in the small molecule TDOs are conserved in NCOs, other active site features and aspects of the overall protein architecture are quite different. Furthermore, the PCOs and ADO appear to act as biological O<jats:sub>2<\/jats:sub> sensors, as shown by kinetic analyses and hypoxic regulation of the stability of their biological targets (N\u2010terminal cysteine oxidation triggers protein degradation via the N\u2010degron pathway). Here, we discuss the emergence of these two subclasses of TDO including structural features that could dictate their ability to bind small molecule or polypeptide substrates. These structural features may also underpin the O<jats:sub>2<\/jats:sub>\u2010sensing capability of the NCOs. Understanding how these enzymes interact with their substrates, including O<jats:sub>2<\/jats:sub>, could reveal strategies to manipulate their activity, relevant to hypoxic disease states and plant adaptive responses to flooding.<\/jats:p>","DOI":"10.1111\/febs.16147","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T08:51:30Z","timestamp":1628067090000},"page":"5426-5439","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Emerging roles for thiol dioxygenases as oxygen sensors"],"prefix":"10.1111","volume":"289","author":[{"given":"Dona M.","family":"Gunawardana","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Oxford  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen C.","family":"Heathcote","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford  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