Adenylyl Cyclase is an enzyme that catalysis the conversion of ATP into Cyclic AMP (cAMP), which acts as a secondary messenger. As the diagram shows below a pyrophosphate molecule is removed in this reaction.
ATP --------------------------------> cAMP + PPi
It's activity is altered through the binding of various hormones, epinephrine, vasopressin and glucagon , to the G-protein_Coupled_Receptor. cAMP in the cell binds to protein kinase A (PKA) activating it. Therefore, adenylyl cyclase has a major role in alterining the activity of enzymes within the cell depending on its own activity i.e how much cAMP it is producing.
It is an integral membrane protein that has the structure of two bundles of six transmembrane segments and two catalytic domains that extend as loops into the cytoplasm, these catalystic domains are also the site of calmodulin binding .
The enzyme can exist in at least 9 isoforms that are regulated in different ways by different G protein coupled receptors. These isoforms can be divided into three groups:
Types I, II and VIII can activated by GαS and Ca2+/calmodulin howvever ALSO can be inhibited by by ßy.
Types II, IV and VII can be activated by GαS and βγ
Types V and VI inhibited by Gαi and free Ca2+.
Role of cAMP
As mentioned above cAMP increases PKA activity, however PKA has different effect in the cells of different oragans. For instance: in adipose tissue epinephrine results in higher cAMP thus incraesed PKA activity and then the PKA phosphorylates the appropriate enzymes resulting in trigylceride hydrolysis. This is different in cardiac muscle where epinephrine activates PKA which phosphorylates proteins/enzymes for increased contraction rate .
Removal of cAMP
PK8 Phosphorylates Phosphodiesterase 3D, which lowers cAMP concerntration in the cells through hydrolysis. PK8 also has a negative feedback effect on PKA, decreasing adenylyl cyclase activity as a result. This lowers cAMP levels even more.
cAMP + H2O ---------------------> 5'AMP + H+(proton)
The mechanism of eprinephrine (signalling molecule) binding to G-protein linked receptor (release of glucose in the "fight or flight" response) can display the roles of adenylyl cyclase and cAMP.
- Eprinephrine binds to transmembrane protein receptor (G-protein linked receptor).
- A conformational change is induced to the receptor causing the alpha subunit of trimeric G-protein to release GDP and bind GTP.
- The activated alpha subunit dissociates from the beta and gamma subunits of the G-protein.
- The alpha subunit with GTP binds to Adenylyl cyclase.
- This converts ATP to cyclic AMP (cAMP).
- The cAMP binds to the regulatory subunit of cAMP dependent protein kinase A. The binding causes a conformational change that releases and activates the catalytic subunit of protein kinase A (PKA).
- Phosphorylation cascades kicks in. PKA catalyses two different routes using phosphorylation.
- PKA inactivates glycogen synthase a and converts it to a phosphorylated glycogen synthase b.
- Another route: PKA phosphorylates phosphorylase kinase. The phosphorylated phosphorylase kinase converts phosphorylase b to a phosphorylated phosphorylase a.
- Phosphorylase a breaks down glycogen into glycogen residue and glucose 1-phosphate, releasing energy.
- Hydrolysis of GTP switches off this signalling pathway.The alpha unit binds GDPand return to its resting state.
- ↑ Heldin and Purton:(1996:223)
- ↑ Active-Site Structure of Class IV Adenylyl Cyclase and Transphyletic Mechanism. D. Travis Gallagher. Journal of Molecular Biology:405(3). (2011)
- ↑ cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Zaccolo M. Br J Pharmacol. 2009 September; 158(1): 50–60
- ↑ British Journal of Pharmacology (2009) 158, 70-86