Emerging roles for thiol dioxygenases as oxygen sensors

Cysteine dioxygenases, 3-mercaptopropionate dioxygenases and mercaptosuccinate dioxygenases are all thiol dioxygenases (TDOs) that catalyse oxidation of thiol molecules to sulphinates. They are Fe(II)-dependent dioxygenases with a cupin fold that supports a 3xHis metal-coordinating 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-terminal cysteinyl dioxygenase enzymes (NCOs) have been identified in plants (plant cysteine oxidases, PCOs), while human 2-aminoethanethiol dioxygenase (ADO) has been shown to act as both an NCO and a small molecule TDO. Although the cupin fold and 3xHis Fe(II)-binding 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 O₂ sensors, as shown by kinetic analyses and hypoxic regulation of the stability of their biological targets (N-terminal cysteine oxidation triggers protein degradation via the N-degron 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 O₂ -sensing capability of the NCOs. Understanding how these enzymes interact with their substrates, including O₂ , could reveal strategies to manipulate their activity, relevant to hypoxic disease states and plant adaptive responses to flooding.