The hunt for transnitrosylase

The biochemical interplay between antioxidants and pro-oxidants maintains the redox homeostatic balance of the cell, which, when perturbed to moderate or high extents, has been implicated in the onset and/or progression of chronic diseases such as diabetes mellitus, cancer, and neurodegenerative diseases. Thioredoxin, glutaredoxin, and lipoic acid-like thiol oxidoreductase systems constitute a unique ensemble of robust cellular antioxidant defenses, owing to their indispensable roles as S-denitrosylases, S-deglutathionylases, and disulfide reductants in maintaining a reduced free thiol state with biological relevance. Thus, in cells subjected to nitrosative stress, cellular antioxidants will S-denitrosylate their cognate S-nitrosoprotein substrates, rather than participate in trans-S-nitrosylation via protein-protein interactions. Researchers have been at the forefront of vaguely establishing the concept of 'transnitrosylation' and its influence on pathophysiology with experimental evidence from in vitro studies that lack proper biochemical logic. The suggestive and reiterative use of antioxidants as transnitrosylases in the scientific literature leaves us on a cliffhanger with several open-ended questions that prompted us to 'hunt' for scientific logic behind the trans-S-nitrosylation chemistry. Given the gravity of the situation and to look at the bigger picture of 'trans-S-nitrosylation', we aim to present a novel attempt at justifying the hesitance in accepting antioxidants as capable of transnitrosylating their cognate protein partners and reflecting on the need to resolve the controversy that would be crucial from the perspective of understanding therapeutic outcomes involving such cellular antioxidants in disease pathogenesis. Further characterization is required to identify the regulatory mechanisms or conditions where an antioxidant like Trx, Grx, or DJ-1 can act as a cellular transnitrosylase.