Adenylyl cyclase

Most class III adenylyl cyclases are transmembrane proteins with 12 transmembrane segments. The protein is organized with 6 transmembrane segments, then the C1 cytoplasmic domain, then another 6 membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site. In Mycobacterium tuberculosis and many other bacterial cases, the AC-III polypeptide is only half as long, comprising one 6-transmembrane domain followed by a cytoplasmic domain, but two of these form a functional homodimer that resembles the mammalian architecture with two active sites. In non-animal class III ACs, the catalytic cytoplasmic domain is seen associated with other (not necessarily transmembrane) domains.^[13]

Class III adenylyl cyclase domains can be further divided into four subfamilies, termed class IIIa through IIId. Animal membrane-bound ACs belong to class IIIa.^[13]: 1087

Mechanism

The reaction happens with two metal cofactors (Mg or Mn) coordinated to the two aspartate residues on C1. They perform a nucleophilic attack of the 3'-OH group of the ribose on the α-phosphoryl group of ATP. The two lysine and aspartate residues on C2 selects ATP over GTP for the substrate, so that the enzyme is not a guanylyl cyclase. A pair of arginine and asparagine residues on C2 stabilizes the transition state. In many proteins, these residues are nevertheless mutated while retaining the adenylyl cyclase activity.^[13]

Types

There are ten known isoforms of adenylyl cyclases in mammals:

These are also sometimes called simply AC1, AC2, etc., and, somewhat confusingly, sometimes Roman numerals are used for these isoforms that all belong to the overall AC class III. They differ mainly in how they are regulated, and are differentially expressed in various tissues throughout mammalian development.

Regulation

Adenylyl cyclase is regulated by G proteins, which can be found in the monomeric form or the heterotrimeric form, consisting of three subunits.^[2][3][4] Adenylyl cyclase activity is controlled by heterotrimeric G proteins.^[2][3][4] The inactive or inhibitory form exists when the complex consists of alpha, beta, and gamma subunits, with GDP bound to the alpha subunit.^[2][4] In order to become active, a ligand must bind to the receptor and cause a conformational change.^[2] This conformational change causes the alpha subunit to dissociate from the complex and become bound to GTP.^[2] This G-alpha-GTP complex then binds to adenylyl cyclase and causes activation and the release of cAMP.^[2] Since a good signal requires the help of enzymes, which turn on and off signals quickly, there must also be a mechanism in which adenylyl cyclase deactivates and inhibits cAMP.^[2] The deactivation of the active G-alpha-GTP complex is accomplished rapidly by GTP hydrolysis due to the reaction being catalyzed by the intrinsic enzymatic activity of GTPase located in the alpha subunit.^[2] It is also regulated by forskolin,^[11] as well as other isoform-specific effectors:

• Isoforms I, III, and VIII are also stimulated by Ca²⁺/calmodulin.^[11]
• Isoforms V and VI are inhibited by Ca²⁺ in a calmodulin-independent manner.^[11]
• Isoforms II, IV and IX are stimulated by alpha subunit of the G protein.^[11]
• Isoforms I, V and VI are most clearly inhibited by Gi, while other isoforms show less dual regulation by the inhibitory G protein.^[11]
• phosphodiesterases, forms local cAMP signalling domains.^[14]

In neurons, calcium-sensitive adenylyl cyclases are located next to calcium ion channels for faster reaction to Ca²⁺ influx; they are suspected of playing an important role in learning processes. This is supported by the fact that adenylyl cyclases are coincidence detectors, meaning that they are activated only by several different signals occurring together.^[15] In peripheral cells and tissues adenylyl cyclases appear to form molecular complexes with specific receptors and other signaling proteins in an isoform-specific manner.

Function

Individual transmembrane adenylyl cyclase isoforms have been linked to numerous physiological functions.^[16] Soluble adenylyl cyclase (sAC, AC10) has a critical role in sperm motility.^[17] Adenylyl cyclase has been implicated in memory formation, functioning as a coincidence detector.^{[11][15][18][19][20]}

Class IV

AC-IV was first reported in the bacterium Aeromonas hydrophila, and the structure of the AC-IV from Yersinia pestis has been reported. These are the smallest of the AC enzyme classes; the AC-IV (CyaB) from Yersinia is a dimer of 19 kDa subunits with no known regulatory components (PDB: 2FJT​).^[21] AC-IV forms a superfamily with mammalian thiamine-triphosphatase called CYTH (CyaB, thiamine triphosphatase).^[22]

Classes V and VI

These forms of AC have been reported in specific bacteria (Prevotella ruminicola O68902 and Rhizobium etli Q8KY20, respectively) and have not been extensively characterized.^[23] There are a few extra members (~400 in Pfam) known to be in class VI. Class VI enzymes possess a catalytic core similar to the one in Class III.^[24]

Additional images

• 
  Beta adrenergic receptor kinase

  pathway

References

Further reading

• Sodeman W, Sodeman T (2005). "Physiologic- and Adenylate Cyclase-Coupled Beta-Adrenergic Receptors". Sodeman's Pathologic Physiology: Mechanisms of Disease. W B Saunders Co. pp. 143–145.
  ISBN 978-0721610108
  .

External links

Wikimedia Commons has media related to Adenylate cyclase.

• Adenylyl Cyclases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Interactive 3D views of Adenylate cyclase at Proteopedia Adenylyl_cyclase