In the cell, adenylyl cyclases and G-proteins interact to catalyze the formation of adenosine 3'-5'-monophosphate (cAMP) from 5'ATP.
Function of G-proteins
In general, a g-protein serves as an intermediary between hormone receptors and effector enzymes. As a result, the g-proteins aid in regulating the metabolism of molecules in response to the hormonal signals and changes. The g-protein complex consists of alpha, beta, and gamma subunits and following disassociation, the separated portions serve functional roles in the activity of the adenylyl cyclases.
When an extracellular hormone binds to the cell receptor, the receptor initiates the ejection of GDP from the G-alpha subunit and initiates the binding of GTP to the G-alpha subunit (2). This results in the disassociation of G-alpha subunit from the G-beta/gamma complex. At this point, both the activated G-alpha subunit and released G-beta/gamma complex can stimulate adenylyl cyclase activity. However, the G-beta/gamma complex can also inhibit the cyclase, only no model for the G-beta/gamma complex's function has been established (3).
Next, the g-alpha subunit with the GTP attached stimulates the adenylyl cyclase by binding to the red region depicted below.
Once bound, the g-alpha subunit
initiates a conformational change, which allows the adenylyl cyclase to
begin its function (6).
Function of the Adenylyl Cyclase
In general, a cyclase serves as an enzyme which catalyzes the cyclization of a compound. Generally, the adenylyl cyclase serves as an effector enzyme, which catalyzes 5'Adenosine Triphosphate (ATP) into cyclic Adenosine Monophosphate (cAMP). In order for the adenylyl cyclase to cyclize the ATP, the G-alpha must be attached to the G-alpha binding site.
Adenylyl Cyclase Type V Complexed
with G-alpha subunit
Once the g-alpha subunit is bound and the adenylyl cyclase undergoes its conformational change, the C1 and C2 catalytic domains of the cyclase become oriented to begin the intake of ATP and cyclization (6).
The process involves the elimination of a pyrophosphate group from the ATP in order to cyclize the AMP, as depicted below.
Once the cAMP is catalyzed, the GTP on the G-alpha converts to GDP and the G-alpha subunit detaches from the cyclase. Once detached, the G-alpha subunit reassociates with the G-beta/gamma complex (6).
The production of more cAMP is carried out when another extracellular hormone attaches to the receptor protein and begins the process once again.
It is also important to note that
there are nine identified isoforms of adenylyl cyclases. All of the
isoforms are activated by G-alpha subunits, however some can be activated
by other molecules such as forskolin or calcium ions. Each of the
isoforms are characterized by distinct biochemical properties and tissue
distribution throughout the body (8). For instance, adenylyl cyclase
type V is found in the heart tissue and adenylyl cyclase type II is found
in the lungs, however adenylyl cyclase type V also functions as a GTPase-activating
protein for G-alpha and enhances the ability of activated receptors to
stimulate GTP-GDP exchange on the G-protein complex (9). In addition
to having various functional abilities, the isoforms also have various
regulation aspects and for more information on the regulation of adenylyl
cyclase isoforms click on the Regulation image below.
1. Image Library of Biological Macromolecules.
2. Weitmann, S., Wursig, N., Navarro, J.M., Kleuss, C. (1999) Biochem. 38, 3409-3413.
3. Weitmann, S., Schultz, G., Kleuss, C. (2001) Biochem. 40, 10853-10858.
4. Purves, Dale. Neuroscience. Sinaner: Massachusetts. 1997: pp 139.
5. Yan, S., Huang, Z., Rao, V., Hurley, J., Tang, W. (1997) J Biol Chem. 272, 18849-18854.
6. Parent, C., Borleis, J., Devreotes, P.N., (2001) J Biol Chem. 10.1074/jbc.M106430200.
7. Tesmer, J. J. G., Sunahara, R. K., Johnson, R. A., Gosselin, G., Gilman, A. G., Sprang, S. R. (1999) Science 285, 756.
8. Onda, T., Hashimoto, Y., Nagai, M. (2001) J Biol Chem. 10.1074/jbc.M107233200.
L., Mullenix, J.B., Wittpoth, C., Poppleton, H.M., Pierre, S.C., Lindorfer,
M.A., Garrison, J.C., and Patel, T.B.
(1999) Science. 283, 1328-1331.
BACK TO TOP