Activators of Soluble Guanylyl Cyclase

Mayer, B., Schmidt, K., Humbert, P. and Bohme, E. Biosynthesis of endothelium-derived relaxing factor a cytosolic enzyme in porcine aortic endothelial cells Ca2+-dependently converts L-arginine into an activator of soluble guanylyl cyclase, Biochem. Biophys. Research Commun. 1989, 164, 678-685. 

Many NO donors, including nitroglycerin, which must be metabolized to release NO (15), are systemic hypotensive agents due to activation of soluble guanylyl cyclase. In vivo studies focusing on the cardiovascular effects of Angeli s... 

As part of the work on model heme FeNO complexes, mechanistic studies on the reversible binding of nitric oxide to metmyoglobin and water soluble Fe, Co and Fe porphyrin complexes in aqueous solution, ligand-promoted rapid NO or NO2 dissociation from Fe porphyrins, reductive nitrosylation of water-soluble iron porphyrins, activation of nitrite ions to carry out O-atom transfer by Fe porphyrins, demonstration of the role of scission of the proximal histidine-iron bond in the activation of soluble guanylyl cyclase through metalloporphyrin substitution studies, reactions of peroxynitrite with iron porphyrins, and the first observation of photoinduced nitrosyl linkage isomers of FeNO heme complexes have been reported. 

Cokic VP, Smith RD, Beleslin-Cokic BB, et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 2003 111 231-239. 

It has been suggested that carbon monoxide (CO) is an activator of soluble guanylyl cyclase in Purkinje cells. Heme oxygenase-2, which degrades heme to biliverdin and releases carbon monoxide in the process, was shown to be co-localized with guanyl cyclase in rat Purkinje and granule cells with in situ hybridization histochemistry (Verma et al., 1993). 

NOS-containing neurons have a very discrete localization in the CNS, representing only 1% of neuronal cells. However, their axons ramify so extensively that virtually every cell in the brain may encounter a NOS nerve terminal. As a diatomic gas, NO is freely diffusible and thus can readily enter adjacent neuronal cells. Once inside the target cell, NO binds the iron in heme contained within the active site of soluble guanylyl cyclase, activating the enzyme to form cyclic guanosine monophosphate (GMP). The activity of NO is therefore mediated by an enzyme receptor. In neurons, NO is formed in response to calcium influx reminiscent of calcium-dependent exocytotic release of neurotransmitters. 

Recently it has been reported that cobinamides can act as co-activators of nitric oxide receptor of soluble guanylyl cyclase by direct binding to the catalytic domain of sGC [338]. This offers new possibilities for its therapeutic applications in augmenting the effect of other sGC-targeting drugs. 

Dierks EA, Burslyn JN. The deactivation of soluble guanylyl cyclase by redox-active agents. Arch Biochem Biophys 1998 351 1—7. 

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