Guanylate cyclase is a
lyaseIn biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
.
It catalyzes the conversion of
guanosine triphosphateGuanosine-5'-triphosphate is a purine nucleotide. It can act as a substrate for the synthesis of RNA during transcription process...
(GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) and
pyrophosphateIn chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Pyrophosphates were originally prepared by heating phosphates: the prefix pyro- derived from Greek, means "fire" in this context. Pyrophosphates are good complexing agents and have many uses in...
:
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 receptor
An enzyme-linked receptor is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side.Are found in all living species....
s:
- GC-A & GC-B for natriuretic factors such as atrial natriuretic factor (ANF).
Guanylate cyclase is a
lyaseIn biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
.
Reaction
It catalyzes the conversion of
guanosine triphosphateGuanosine-5'-triphosphate is a purine nucleotide. It can act as a substrate for the synthesis of RNA during transcription process...
(GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) and
pyrophosphateIn chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Pyrophosphates were originally prepared by heating phosphates: the prefix pyro- derived from Greek, means "fire" in this context. Pyrophosphates are good complexing agents and have many uses in...
:
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 receptor
An enzyme-linked receptor is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side.Are found in all living species....
s:
- GC-A & GC-B for natriuretic factors such as atrial natriuretic factor (ANF). (NPR1
Natriuretic peptide receptor A/guanylate cyclase A , also known as NPR1, is a protein that in humans is encoded by the NPR1 gene.- Function :...
/GUCY2A, NPR2Natriuretic peptide receptor B/guanylate cyclase B , also known as NPR2, is a protein that in humans is encoded by the NPR2 gene....
/GUCY2B)
- GC-C for guanylin
Guanylin is a 15 amino acid peptide that is secreted by goblet cells in the colon. Guanylin acts as an agonist of the guanylyl cyclase receptor GC-C and regulates electrolyte and water transport in intestinal and renal epithelia....
and uroguanylinUroguanylin is a 16 amino acid peptide that is secreted by enterochromaffin cells in the duodenum and proximal small intestine. Guanylin acts as an agonist of the guanylyl cyclase receptor GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.In humans, the...
. (See also guanylyl cyclase cGuanylyl cyclase c, or GC-C, is an enzyme found only in the luminal aspect of intestinal epithelium. The receptor has an extracellular ligand-binding domain, a single transmembrane region, a region with sequence similar to that of protein kinases, and a C-terminal guanylyl cyclase domain...
). (GUCY2C)
- Others: (GUCY2D
GUCY2D is a guanylate cyclase associated with type 1 Leber's congenital amaurosis....
, GUCY2E, GUCY2F)
Soluble
Soluble guanylyl cyclase (sGC) is a receptor for
NONitric oxide or nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals, including humans, and is an extremely important intermediate in the chemical industry...
(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
GUCY1A2Guanylate cyclase soluble subunit alpha-2 is an enzyme that in humans is encoded by the GUCY1A2 gene.-Further reading:...
,
GUCY1A3Guanylate cyclase soluble subunit alpha-3 is an enzyme that in humans is encoded by the GUCY1A3 gene.-Further reading:...
, GUCY1B2 and
GUCY1B3Guanylate cyclase soluble subunit beta-1 is an enzyme that in humans is encoded by the GUCY1B3 gene.-Interactions:GUCY1B3 has been shown to interact with Heat shock protein 90kDa alpha , member A1 and Endothelial NOS.-Further reading:...
.
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 oxideNitric oxide or nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals, including humans, and is an extremely important intermediate in the chemical industry...
, 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.
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
, two drugs activating sGC are under investigation for the treatment of pulmonary arterial hypertension:
cinaciguatCinaciguat is an experimental drug for the treatment of acute decompensated heart failure.-Mechanism of action:Cinaciguat activates the soluble guanylate cyclase which is a receptor for nitric oxide...
and
riociguatRiociguat is an experimental drug for the treatment of pulmonary arterial hypertension. , it is undergoing Phase III clinical trials.-Mechanism of action:...
.
Function
Once formed, cGMP can be degraded by
phosphodiesteraseA phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
s, which themselves are under different forms of regulation, depending on the tissue.
Like
cAMPCAMP may stand for:* Cyclic adenosine monophosphate * Cathelicidin antimicrobial peptide* Campaign Against Marijuana Planting* Central Atlantic Magmatic Province* CAMP, an Italian manufacturer of climbing equipment....
, cGMP is known to regulate many cellular proteins, such as
protein kinaseA protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s,
ion channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of all living cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s, and phosphodiesterases.