A paradigm-expanding role for albumin: Metal-free, protein-mediated nitrite bioactivation

Nitric oxide (NO) radical has remarkable importance due to its involvement in virtually all physiological and pathophysiological processes. It is a critical regulatory mediator and effector molecule of the cardiovascular-, nervous- and immune systems. Nitrite is recognized as a biologic reservoir of NO bioactivity. The nitrite-to-NO conversion that enables the release and signaling competence of NO is traditionally attributed to heme-containing proteins. Here, we demonstrate that human serum albumin, the most abundant plasma protein, can also mediate the conversion of nitrite to NO via its conserved cysteine-34 residue. We propose that upon oxidation to sulfenic acid, Cys-34 reacts with nitrite to form a sulfenyl nitrite intermediate, which decomposes to liberate bioactive NO. This unveils a previously unrecognized, non-heme, protein-based route for nitrite bioactivation and expands our understanding of NO homeostasis. These findings introduce new perspectives for therapeutic modulation of redox signaling pathways and reshapes the understanding of NO generation in biological systems.