Soluble guanylyl cyclase (E.C. 4.6.1.2)

Overview: Soluble guanylyl cyclase [GTP diphosphate-lyase (cyclizing)] is a heterodimer comprising αand βchains, both of which have two subtypes in man (predominantly α1β1; see Zabel et al., 1998). A heme group is associated with the β chain and is the target for the endogenous ligand nitric oxide (NO•), and, potentially, carbon monoxide (Friebe et al., 1996). The enzyme converts guanosine-5′-triphosphate (GTP) to the intracellular second messenger 3′,5′-guanosine monophosphate (cGMP).

Nomenclature	Soluble guanylyl cyclase
Preferred abbreviation	sGC
Ensembl ID	α1 ENSG00000164116; α2 ENSG00000152402; β1 ENSG00000061918; β2 ENSG00000123201
Selective activators	NO•, YC1 (Friebe et al., 1996), BAY412272 (Stasch et al., 2001), BAY582667 (Stasch et al., 2002)
Selective inhibitors	ODQ (7.5; Garthwaite et al., 1995)

ODQ also shows activity at other heme-containing proteins (Feelisch et al., 1999), while YC1 may also inhibit cGMP-hydrolysing phosphodiesterases (Friebe et al., 1998; Galle et al., 1999).

Glossary

Abbreviations:

BAY412272

5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine)

BAY582667

4-([4-carboxybutyl][2-{(4-phenethylbenzyl)oxy}phenethyl]amino)methyl(benzoic)acid

ODQ

1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one

YC1

3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole HMR1766

Further Reading

Cary SP, Winger JA, Derbyshire ER, Marletta MA (2006). Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci31: 231–239.

Cerra MC, Pellegrino D (2007). Cardiovascular cGMP-generating systems in physiological and pathological conditions. Curr Med Chem14: 585–599.

Doggrell SA (2005). Clinical potential of nitric oxide-independent soluble guanylate cyclase activators. Curr Opin Investig Drugs6: 874–878.

Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP (2006). NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov5: 755–768.

Jackson EB, Mukhopadhyay S, Tulis DA (2007). Pharmacologic modulators of soluble guanylate cyclase/cyclic guanosine monophosphate in the vascular system – from bench top to bedside. Curr Vasc Pharmacol5: 1–14.

Moncada S, Higgs EA (2006). Nitric oxide and the vascular endothelium. Handb Exp Pharmacol176: 213–254.

Poulos TL (2006). Soluble guanylate cyclase. Curr Opin Struct Biol16: 736–743.

Pyriochou A, Papapetropoulos A (2005). Soluble guanylyl cyclase: more secrets revealed. Cell Signal17: 407–413.