Mechanisms of Cysteine‐Lysine Covalent Linkage—The Role of Reactive Oxygen Species and Competition with Disulfide Bonds

• Published in: Angewandte Chemie 2023-09, Vol.135 (36), p.n/a
• Main Authors: Ye, Jin, Bazzi, Sophia, Fritz, Tobias, Tittmann, Kai, Mata, Ricardo A., Uranga, Jon
• Format: Article
• Language: English
• Subjects: Chemical bonds; Chemistry; Cysteine; Density Functional Theory; Disulfide bonds; Electronic structure; Intermediates; Lysine; NOS; Oxidation; Oxygen; Reaction Mechanisms; Reactive Oxygen Species; Reagents; Reducing agents
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202304163

Recently, a new naturally occurring covalent linkage was characterised, involving a cysteine and a lysine, bridged through an oxygen atom. The latter was dubbed as the NOS bond, reflecting the individual atoms involved in this uncommon bond which finds little parallel in lab chemistry. It is found to form under oxidising conditions and is reversible upon addition of reducing agents. Further studies have identified the bond in crystal structures across a variety of systems and organisms, potentially playing an important role in regulation, cellular defense and replication. Not only that, double NOS bonds have been identified and even found to be competitive in relation to the formation of disulfide bonds. This raises several questions about how this exotic bond comes to be, what are the intermediates involved in its formation and how it competes with other pathways of sulfide oxidation. With this objective in mind, we revisited our first proposed mechanism for the reaction with model electronic structure calculations, adding information about the reactivity with alternative reactive oxygen species and other potential competing products of oxidation. We present a network with more than 30 reactions which provides one of the most encompassing pictures for cysteine oxidation pathways to date. An unusual “NOS” bond with a bridging oxygen atom can form under oxidising conditions between a cysteine and a lysine residue. Now the reaction mechanisms for the formation of single and double NOS bonds in proteins have been computationally investigated. More than 30 reactions were considered for oxidation pathways involving different reactive oxygen species, providing a comprehensive overview of cysteine oxidation pathways.