Abstract
Nitric oxide (NO) is a highly reactive molecule, generated through metabolism of L-arginine by NO synthase (NOS). Abnormal NO levels in mammalian cells are associated with multiple human diseases, including cancer. Recent studies have uncovered that the NO signaling is compartmentalized, owing to the localization of NOS and the nature of biochemical reactions of NO, including S-nitrosylation. S-nitrosylation is a selective covalent post-translational modification adding a nitrosyl group to the reactive thiol group of a cysteine to form S-nitrosothiol (SNO), which is a key mechanism in transferring NO-mediated signals. While S-nitrosylation occurs only at select cysteine thiols, such a spatial constraint is partially resolved by transnitrosylation, where the nitrosyl moiety is transferred between two interacting proteins to successively transfer the NO signal to a distant location. As NOS is present in various subcellular locales, a stress could trigger concerted S-nitrosylation and transnitrosylation of a large number of proteins involved in divergent signaling cascades. S-nitrosylation is an emerging paradigm of redox signaling by which cells confer protection against oxidative stress.
Highlights
In the past decades, nitric oxide (NO) has garnered an increasing amount of interest with regard to its impact on many human diseases
Cumulative evidence suggests that S-nitrosylation plays a large part in Nitric oxide (NO)-mediated biological activities [11]
The nitrosyl group could travel to different subcellular locales through a cascade of transnitrosylation reactions [58]
Summary
Nitric oxide (NO) has garnered an increasing amount of interest with regard to its impact on many human diseases. In the presence of high levels of reactive oxygen species (ROS), such as superoxide, NO reacts with ROS and forms a strong oxidant, reactive nitrogen species, which in turn reacts with and oxidatively damages a variety of biological molecules. This mode of NO effect is said to be “indirect”. NO signaling, NO binds the heme iron of guanylyl cyclase (sGC) to induce production of cGMP, which activates the cGMP-dependent protein kinase (PKG) pathway [10] Notwithstanding this classical scheme, recent studies have unveiled a wealth of “non-classical” NO signaling that mediates pleiotropic functions in diverse tissues/organs. We will discuss how dysregulated S-nitrosylation would lead to disease conditions
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