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

Abstract

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.

A Cell‐Permeable Photosensitizer for Selective Proximity Labeling and Crosslinking of Aggregated Proteome

“…We scrutinized the tandem mass spectrometry results of labeled peptides and deduced different types of modification mechanisms, including the recently reported N‐O‐S reaction (Figure 4G,H ; Figure S16 , Supporting Information). [ 17 ] Additionally, lysine, a readily labeled amino acid using the singlet electron transfer (SET) labeling mechanism, was also observed to be extensively labeled in this study (Figure 4I ; Figure S33 , Supporting Information). [ 18 ] Importantly, different from previous reports, histidine was not top‐ranked in P5 enabled proximity labeling (Figure 4I ; Figure S20 , Supporting Information).…”

Nanoscale 0D/1D Heterojunction of MAPbBr3/COF Toward Efficient LED-Driven S–S Coupling Reactions

“…Disulfide bonds 1,2 hold multiples essential roles in life science, 3 protein folding, 4,5 pharmacy, 6−8 material science, 9 and advanced chemical application 10,11 due to their superior reversibility, flexibility, and stability. Specifically, the stable covalent bond of S−S and flexible ligands enable threedimensional folding and cross-linking, 12 which contribute to the assembly of proteins from polypeptides and the vulcanization of polymer rubber. 13 Meanwhile, the expression and realization of biological functions stored in genes are also controlled by S−S in various proteins.…”

“…Disulfide bonds , hold multiples essential roles in life science, protein folding, , pharmacy, − material science, and advanced chemical application , due to their superior reversibility, flexibility, and stability. Specifically, the stable covalent bond of S–S and flexible ligands enable three-dimensional folding and cross-linking, which contribute to the assembly of proteins from polypeptides and the vulcanization of polymer rubber . Meanwhile, the expression and realization of biological functions stored in genes are also controlled by S–S in various proteins. , It also plays a pivotal role in the encapsulation, delivery, and release over time of targeted antitumor drugs, as well as chemical organic synthesis. , Therefore, the precise synthesis and management of S–S hold promise for the scaled-up application of disulfide-bond-based medical and functional materials.…”

In Solution Identification of the Lysine–Cysteine Redox Switch with a NOS Bridge in Transaldolase by Sulfur K-Edge X-ray Absorption Spectroscopy

“…10,11 Moreover, computational insights have also been laid out on exploratory reaction mechanisms of the formation of the NOS bridge. 12 Even though the NOS bridge's chemical identity was clearly shown by protein crystallography at sub-ångstrom resolution, its presence in solution has so far never been directly demonstrated. Previous studies with mass spectrometry suggested that the NOS bridge dissolves following the proteolytic processing of the protein prior to the measurements.…”

“…This causes a reconfiguration of key catalytic residues evoking an increase in enzymatic activity by several orders of magnitude . Further studies have identified the NOS switch in crystal structures across a variety of systems and organisms including SARS-CoV-2, potentially playing an important role in regulation, cellular defense, and replication. , Moreover, computational insights have also been laid out on exploratory reaction mechanisms of the formation of the NOS bridge …”