Guanylate cyclase

Guanylate cyclase (EC 4.6.1.2, also known as guanylyl cyclase, guanyl cyclase or GC) is a lyase enzyme.

Reaction

It catalyzes the conversion of guanosine triphosphate (GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) and pyrophosphate:

GTP

cGMP

Types

There are membrane-bound (type 1) and soluble (type 2) forms of guanylyl cyclases.

Membrane-bound

Membrane-bound guanylyl cyclase is a single transmembrane protein and acts as an ANP receptor (compare it with Adenylate Cyclase which is 12 transmembrane protein).

• Another type of Type 1 receptor binds to the ST E Coli enterotoxin and the gastrointestinal polypeptide Guanylin.
• Membrane-bound forms are enzyme-linked receptors:
  • GC-A & GC-B for natriuretic factors such as atrial natriuretic factor (ANF). (NPR1/GUCY2A, NPR2/GUCY2B)
  • GC-C for guanylin and uroguanylin. (See also guanylyl cyclase c). (GUCY2C)
  • Others: (GUCY2D, GUCY2E, GUCY2F)

Soluble

Soluble guanylyl cyclase (sGC) is a receptor for NO (thus also called NO receptor). It is soluble, i.e. completely intracellular. It is most notably involved in vasodilation. In humans, it is encoded by the genes GUCY1A2, GUCY1A3, GUCY1B2 and GUCY1B3.

Structure

sGC is a heterodimer composed of one alpha (1, 2) and one heme-binding beta (1, 2) subunits. Each domain contains a C terminal cyclase domain. The enzyme has one heme per dimer, with a proximal histidine ligand located in the N terminal region of the beta 1 subunit. In its Fe(II) form, this heme moiety is the target of nitric oxide, which is synthesized by endothelial cells following appropriate stimulation. The 250 residue C-terminal catalytic domain is highly conserved in soluble and membrane bound guanylyl cyclases, as well as adenylyl cyclases.

sGC also contains a PAS type regulatory domain. Named after the first three proteins in which it was found (Period clock protein, ARNT protein, and Single minded protein) the PAS domain is a sensor domain that has been found in a large variety of proteins, and can work in conjunction with a variety of prosthetic groups as a sensor for a variety of conditions, including light, oxidative stress, or diatomic gasses, in this case in conjunction with a heme group in the sensing of nitric oxide. While the PAS domain of sGC has no available structure, the PAS domains of several other proteins have been crystallized.

Regulation

NO leads to a 400 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 [NO] 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.^[1]

Upon oxidative stress, Fe(II)sGC can be oxidised and lose its heme. Heme-free (apo-sGC) is no longer rtesponsive to NO but to so-called sGC activator compounds. The latter bind to the empty heme pocket and exert an activation that is similar to that 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.

Soluble GC as drug target

As of April 2008^[update], two drugs activating sGC are under investigation for the treatment of pulmonary arterial hypertension: cinaciguat and riociguat.

Function

Once formed, cGMP can be degraded by phosphodiesterases, which themselves are under different forms of regulation, depending on the tissue.

Like cAMP, cGMP is known to regulate many cellular proteins, such as protein kinases, ion channels, and phosphodiesterases.

See also

• Guanylate cyclase activator (protein)

References

External links

• MeSH Guanylate+Cyclase