Soluble Guanylyl Cyclase - Regulation

Regulation

NO leads to at least 200 fold increase in sGC activity. Because nitric oxide has a partially filled pi* orbital, back bonding prefers a bent geometry for the heme-NO complex. NO has a strong trans effect, in which the histidine-iron bond is weakened when NO binding delocalizes electrons to the dz2 orbital toward the axial ligand. Thus nitric oxide binding ferrous heme at the distal position gives a His-Fe-NO complex that dissociates to a 5-coordinate Fe-NO complex. However, the identification of two distinct dependent processes in sGC activation has led to speculation that a proximal NO is responsible for histidine displacement, giving an intermediate 6-coordinate NO-Fe-NO complex. Depending on product concentration, the intermediate can then dissociate either to one of two 5-coordinate forms, the more active distally NO ligated form, or the less active proximally NO ligated form. An alternative hypothesis states that a second, non-heme binding site accounts for the second NO dependent activation process to give the fully active enzyme.

Under conditions of oxidative stress, Fe(II)sGC can be oxidized and lose its heme. Heme-free (apo-sGC) no longer responds to NO, but does respond to so-called sGC activator compounds. The latter bind to the empty heme pocket and activate the enzyme in a similar manner to the activation of Fe(II)sGC by NO.

In addition, sGC contains an allosteric site, to which sGC stimulators bind. They potentiate NO-sGC signalling, so that sub-maximally active concentrations of NO reach a maximal activation of sGC. On their own, sGC stimulators have only a marginal effect on sGC.