Adenylate Cyclase

Definition
Adenylate cyclase (AC) or adenylyl cyclase or 3¢, 5¢ -cyclic AMP synthetase is a lyase enzyme. It initiates the conversion of adenosine triphosphate to cyclic adenosine monophosphate, a mediator of many physiologic activities. It is activated by the attachment of a hormone or neurotransmitter to a specific membrane-bound receptor.

Discovery
Reik and team were the first to report the histochemical localization of AC using a modification of the lead capture procedure popularized by Wachstein and Meisel, in this procedure ATP was used as a substrate and lead ions as the capture agent1.

Classification

Ten isoforms of mammalian AC are known, numbered from AC1-AC9 and soluble adenylyl cyclase (SAC). SAC are found in the nucleus, mitochondria and microtubules2.

Structural Characteristics

AC is an integral membrane protein that consists of two bundles of six transmembrane segments. Hormone-sensitive AC systems are composed of hormone-recognition units (R), a nucleotide-regulatory unit (N) for reaction with GTP and divalent cations, and the catalytic unit (C)3. The catalytic cytosolic regions of mammalian ACs also share significant sequence similarity to the corresponding regions of guanylyl cyclase (GCs)4. Two catalytic domains, the palm domain and the adenylyl cyclase catalytic core (ACYc) domain extend as loops into the cytoplasm.

Mode of action

Adenylate cyclase is stimulated by G proteins, forskolin as well as other class-specific substrates; G proteins are coupled to membrane receptors and responds to hormonal stimulus. Following activation of adenylate cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels. . Epinephrine, dopamine, prostaglandin PGE2, adenosine, and glucagon are a few examples of the many hormones that activate AC through membrane-bound receptors. Glucagon-bound receptors communicate with an intracellular, membrane-associated heterotrimeric G protein composed of a guanosine diphosphate (GDP)–bound α-subunit and an obligate βγ heterodimer. Hormone-dependent activation of receptors leads to the exchange of GDP for guanosine triphosphate (GTP). Conformational changes due to GTP binding result in the dissociation of the heterotrimeric G protein into a and By subunits, which then interact with their respective effectors4.

Functions

AC through the production of cyclic AMP (cAMP) can transduce dual signals, positive and negative, on cell growth and differentiation. Such dual signals are transmitted by RI and RII cAMP-binding receptor proteins respectively, the regulatory subunits of cAMP dependent protein kinases. The growth stimulatory RI and inhibitory RII are in a strict balance to maintain normal cells, and departure from such balance can cause a great variety of human diseases, including cancer. Experimental approaches using site-selective cAMP analogues, antisense oligodeoxynucleotides, and gene transfer have shown that restoration of the normal balance of RI/RII provides a biological means to the suppression of malignancy5.

References

1. Cutler LS, Christian CP (1980). Cytochemical Localization of Adenylate Cyclase. The Journal of Histochemistry and Cytochemistry, 28(1):62-65.
2. Feng Q, Zhang Y, Li Y, Liu Z, Zuo J, Fang F (2006). Two domains are critical for the nuclear localization of soluble adenylyl cyclase. Biochimie, 88 (3-4):319-28.
3. Rodbell M (1982). Structure-function relationships in adenylate cyclase systems. Ciba Found Symp, 90:3-21.
4. Roger K. Sunahara and Ron Taussig (2002). Isoforms of Mammalian Adenylyl Cyclase. Molecular interventions, 2 (3):168-184
5. Cho-Chung YS (1992). Modulation of adenylate cyclase signalling. Semin Cancer Biol., 3 (6):361-367.