Figure 1.

The roles of cGMP and S-nitrosylation in NO-based signaling (A) and enzymatic protein denitrosylation mediated by the S-nitrosoglutathione reductase (GSNOR) and thioredoxin (Trx) systems (B). (A) NO synthase (NOS) synthesizes NO, which may activate soluble guanylyl cyclase and thereby enhance production of cGMP (left) or subserve protein S-nitrosylation (right). The cGMP-dependent pathway is deactivated by cGMP-phosphodiesterase (PDE), which hydrolyzes cGMP to GMP (PDE may also be activated allosterically by cGMP). The SNO-based mechanisms are dynamically regulated via S-nitrosylation and denitrosylation of a multitude of cysteine-containing proteins. In contrast to the multiple elements regulated by S-nitrosylation, the cGMP-based signaling system relies primarily on the cGMP-dependent protein kinase, PKG. (B) Proteins undergo reversible S-nitrosylation and denitrosylation (center). Denitrosylation mediated by GSNOR is depicted on the left. Transnitrosylation of glutathione (GSH) by S-nitrosylated proteins generates GSNO and native protein. GSNO undergoes NADH-dependent reduction by GSNOR to generate glutathione S-hydroxysulfenamide (GSNHOH), which can undergo further reaction with GSH to generate oxidized glutathione (GSSG). The redox cycle is completed by reduction of GSSG to GSH via GSSG reductase. Denitrosylation mediated by the thioredoxin (Trx) system is depicted on the right. The active site dithiol motif (CXXC) of Trx1 (cytoplasmic) or Trx2 (mitochondrial) undergoes oxidation coupled to denitrosylation of SNO substrate. Oxidized Trx is reduced by the selenoprotein thioredoxin reductase (TrxR), which employs the reducing power of NADPH to regenerate active Trx.