Soluble Guanylate Cyclase

Abstract

Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this. Article see p 2781 Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention. The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Figure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC …