Nitrosothiol formation and S-nitrosation signaling through nitric oxide synthases

Nitric Oxide. 2017 Feb 28;63:52-60. doi: 10.1016/j.niox.2016.10.001. Epub 2016 Oct 5.


Nitric oxide (NO) is a gaseous signaling molecule impacting many biological pathways. NO is produced in mammals by three nitric oxide synthase (NOS) isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS and eNOS produce low concentrations of NO for paracrine signaling; NO produced and released from one cell diffuses to a neighboring cell where it binds and activates soluble guanylyl cyclase (sGC). iNOS produces high concentrations of NO using NO toxicity to amplify the innate immune response. Recent work has also defined protein cysteine S-nitrosation as a pathway of sGC-independent NO signaling. Though many studies have shown that S-nitrosation regulates the activity of NOS isoforms and other proteins in vivo, many issues need to be resolved to establish S-nitrosation as a viable signaling mechanism. Several chemical mechanisms result in S-nitrosation including transition metal-catalyzed pathways, NO oxidation followed by thiolate reaction, and thiyl radical recombination with NO. Once formed, nitrosothiols can be transferred between cellular cysteine residues via transnitrosation reactions. However, it is largely unclear how these chemical processes result in selective S-nitrosation of specific cellular cysteine residues. S-nitrosation site selectivity may be imparted via direct interactions or colocalization with NOS isoforms that focus chemical or transnitrosation mechanisms of nitrosothiol formation or transfer. Here, we discuss chemical mechanisms of nitrosothiol formation, S-nitrosation of NOS isoforms, and potential S-nitrosation signaling cascades resulting from NOS S-nitrosation.

Keywords: Nitric oxide; Nitric oxide synthase; Nitrosothiol; S-nitrosation; S-nitrosylation.

Publication types

  • Review

MeSH terms

  • Animals
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Humans
  • Nitric Oxide Synthase / chemistry
  • Nitric Oxide Synthase / metabolism*
  • Nitrosation
  • S-Nitrosothiols / chemistry
  • S-Nitrosothiols / metabolism*
  • Signal Transduction / physiology*


  • S-Nitrosothiols
  • Nitric Oxide Synthase
  • Cysteine