The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

Abstract

S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis

“…However, the different degree of inhibition of GSNOR activities under conditions with pharmacological inhibitor (N6022) vs. genetic elimination of GSNOR (GSNOR knockout mice) may account, at least in part, for these observed differences. Secondly, GSNOR degrades a number of other compounds in addition to GSNO [73] and this may also account for these observed differences.…”

Hiding in Plain Sight: Nebivolol Exhibits Compelling Tocolytic Properties

“…Nebivolol further enhances endothelial nitric oxide synthase ( eNOS ) expression and activity . This resulting surge of nitric oxide increases total protein S‐nitrosations ( SNO s), promoting SNO ‐mediated myometrial smooth muscle relaxation . Inhibition of S‐nitrosoglutathione reductase ( GSNOR ) also increases nitric oxide availability, which relaxes myometrial tissue; however, nebivolol does not inhibit the SNO ‐metabolizing enzymes GSNOR or thioredoxin reductase (TrxR)…”

“…•NO is a critical mediator of uterine quiescence; however, •NO's most pervasive role in the myometrium is through protein S‐nitrosation (SNO), rather than cGMP accumulation. S‐nitrosoglutathione reductase (GSNOR) is an important modulator of •NO and S‐nitrosation . GSNOR is upregulated in human sPTL myometrium, and inhibition of GSNOR by N6022 can partially restore native myometrial function …”

S‐nitrosylation of cytoskeletal proteins

“…In vivo, glutathione and the enzyme nitrosoglutathione reductase (alcohol dehydrogenase 3) can speed the denitrosation reaction (Barnett & Buxton, 2017;Staab, Ålander, Morgenstern, Grafström, & Höög, 2009). In vivo, glutathione and the enzyme nitrosoglutathione reductase (alcohol dehydrogenase 3) can speed the denitrosation reaction (Barnett & Buxton, 2017;Staab, Ålander, Morgenstern, Grafström, & Höög, 2009).…”