Soluble guanylate cyclase activation mechanism

Dimethyl-l,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (41) is also an old product [7,11, 31] that has recently been found to react with GSH to give S-nitrosogluta-thione, NO and HNO [32]. It stimulates partially purified rat lung soluble guanylate cyclase, but not the heme-deficient enzyme. The activation is inhibited by ODQ. The product also displays significant vasodilator activity on rat thoracic aorta rings at nanomolar concentrations. Finally, [l,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide derivatives (42, R,Ri=CH3,H) release NO, detected as nitrite, in the presence of thiols. A mechanism for this release has been proposed [33]. 

DETA/NO is a stable NO-donor with the longest NO generation half-life of approximately 20 h. Thrombelastography performed on rabbit blood showed that DETA NONOate-derived NO significantly decreased coagulation activity and platelet activation [48]. Monitoring by intravital microscopy showed that DETA/NO attenuated the platelets/endothelial cells adhesion response to endotoxins (e.g. lipopolysaccharides) in murine intestinal venules [49]. The main mechanism of the antiadhesive action of DETA/NO on platelets was activation of soluble guanylate cyclase [49]. 

The mechanism of activation of the receptor-type guanylate cyclases is not entirely clear. As is the case with other single-transmembrane domain receptor types, such as receptor-type tyrosine kinases, some sort of dimerization may be induced by ligand binding, which serves to activate the intracellular enzyme part of the receptor. As discussed in the next section, dimerization is essential to enzyme activity in soluble guanylate cyclases. 

Guanylate cyclase [GTP pyrophosphate-lyase (cyclizing) EC 4.6.1.2.] can be purified as soluble and particulate isozyme forms from most mammalian tissues. While both isozyme families catalyze the formation of cGMP from GTP, they are structurally different proteins. Their mechanism of activation and their kinetic and physicochemical properties differ markedly from each other. Soluble guanylate cyclase (sGC) has been shown to exist as a heterodimer with protein subunits of 70 and 82 kDa and has a native... 

Wolin M, Burke T. Hydrogen peroxide elicits activation of hovine pulmonary arterial soluble guanylate cyclase by a mechanism associated with its metaholism hy catalase. Biochem Biophys Res Commun 1987 143 20-25. 

Figure 2 Potential relationships between NAD(P)H-derived ROS, redox systems, and signaling mechanisms regulated by PO2 in vascular smooth muscle. LDH, lactate dehydrogenase GSH red, glutathione reductase GSH Px, glutathione peroxidase RNS, reactive nitrogen species SOD, superoxide dismutases sGC, soluble guanylate cyclase MAPK, mitogen-activated protein kinases.

Severina, I.S., Bussygina, O.G., Vinograd, L.H., and Grigoryev, N.B. (1996). Mechanism of activation of soluble guanylate cyclase by guanidine thiols - A new class of enzyme activators. Biochem. Mol. Biol. Int. 38, 509-518. 

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