Adenylate cyclase

Adenylyl cyclases (AC ), formerly adenylate belong to the class of lyases, namely molecule- cleaving enzymes.

In higher organisms, they are important mediators between hormones or other chemical messengers that bind to the outside of the cell membrane, and cell internal messengers ( second messenger, " second messenger " ), which forward the action of these hormones within the cell.

In the process of signal transduction initially binds the hormone to a matching G- protein-coupled receptor. This releases the corresponding G protein, which in turn activates adenylyl cyclase. This then forms the interior of the cell to the second messenger cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).

Adenylyl cyclases are found in almost all living things. When people are aware of their current ten, mainly bound to the cell membrane isoenzymes.

Occurrence

Adenylyl cyclases are widely used in living nature. Even simple unicellular eukaryotic organisms such as Paramecium, Euglena and Dictyostelium as well as some prokaryotes use adenylylcyclases for the conversion of ATP to cAMP. In addition, take advantage of some prokaryotic pathogens the function of adenylyl cyclases or cAMP higher organisms, forming itself adenylyl cyclases or activators of adenylyl cyclases and release. For example, the invasiveness of the cholera pathogen Vibrio cholerae is due to the adenylyl cyclases indirectly activating cholera toxin. The liberated adenylyl cyclases of Bordetella pertussis and Bacillus anthracis, which are activated in the body of the host organism are part of their toxic principle.

Classification

The adenylyl cyclases belong to the group of lyases. Classically, the adenylyl cyclases are divided into three main classes. Class I includes the adenylyl cyclases of gram-negative bacteria. Adenylylcyclases Class II play as toxic proteins of prokaryotic pathogens involved are from the protein calmodulin dependent of the host organism. Numerically, the largest are the adenylyl cyclases class III. It includes all eukaryotic adenylyl cyclases as well as numerous prokaryotic enzymes. Rare further three classes (IV -VI) mentioned by adenylyl cyclases.

The adenylyl cyclases of people comprise 10 different isoenzymes and be as AC1 to AC10 designated (or AC I to AC X). The isoenzymes AC1 to AC9 are membrane-bound proteins. Also known as the sAC ( soluble adenylyl cyclase from ) designated isoenzyme AC10 is a cytosolic protein found predominantly localized in specific cellular compartments. In addition, the isozymes of adenylyl cyclases differ in their regulatory mechanisms.

* Activation, oh no effect - inhibition; Ca2 effects at low (<1 uM ) Ca2 concentrations

Structure

The occurring in living nature adenylylcyclases follow partly very different construction plans. All have in common that they carry at least one essential for the function cyclase homology domain. The membrane-bound adenylyl cyclases multicellular animals ( Metazoa ) consist of two transmembrane domains, each with six α -helices (M1 and M2) and two cytosolic cyclase homology domains (C1 and C2). The two approximately 40 kDa cyclase homology domains can be further in catalytic ( C1a and C2a ) and regulatory subdomains divide ( C1b and C2b ). The catalytic subdomains exhibit a high degree of homology.

The three-dimensional structure of the catalytic subdomains of various animal adenylyl cyclases could be elucidated by X-ray structural analysis. This technique could be used for the catalytic subdomains one consisting of a βαββαβ motif structure, which for example is also found in some DNA polymerases, are confirmed. Both catalytic domains interact with each other to form a functional unit. At the contact side of the two subunits, the formed C1a C2a unit has a groove with a binding site for the substrate ATP. Also in this furrow is another binding site for the activator forskolin, a diterpene from Plectranthus barbatus the harp shrub contain. The binding site for the stimulatory G protein Gs and golf comprises a small proportion of the N-terminus of subdomain C1a and a larger proportion of C2a subdomain. In addition, another binding site is believed to regulatory C1b subdomain. Postulated binding site for inhibitory G proteins (Gi / o family) at the C1a subdomain is different from the binding site stimulating G- proteins.

Function

Adenylyl cyclase catalyzes the formation of cAMP from ATP elimination of pyrophosphate. Depending on the isoenzyme to be implemented by a molecule of between one and adenylyl cyclase 100 substrate molecules per second. The respective Michaelis constants Km, which correspond to the substrate concentration at half-maximal reaction rate, amount to between 30 and 400 uM.

In vertebrates and invertebrates (eg, Aplysia ) cAMP acts as a second messenger. The enzyme is therefore a part of the signal cascade for the routing of signals within cells. It is also often associated with a stimulation of transmitter release and the signal transmission, with an increase in heart rate and smooth muscle relaxation. The adenylyl cyclase is thus responsible for the transmission of stimuli, as well as for the effects of numerous hormones (such as glucagon and adrenaline) and neurotransmitters (such as serotonin).

Regulation

In the human organism the activity of adenylyl cyclases is particularly physiologically regulated by the G- proteins involved in signal transduction. Stimulatory G proteins of the Gs / olf family favor a closed conformation of the dimeric catalytic unit of adenylyl cyclase and thus activate the enzyme function. Inhibitory Gi / o proteins cause a stabilization of the open conformation to an inhibition of Adenylylcyclasefunktion. Some isoforms of adenylyl cyclase (AC1, AC3 and AC8 ) are also regulated by calcium / calmodulin.

In addition, the adenylyl cyclases can be regulated pharmacologically. The diterpene forskolin is a non-selective activator of adenylyl cyclases, which activates all human adenylyl cyclases with the exception of AC9. The discovery that adenosine selectively inhibits not all adenylyl cyclases, led to development of numerous nucleoside and nucleotide Ananloga. They usually lead a so-called P -site inhibitors of adenylyl cyclases to a non- or uncompetitive inhibition, which is based on different mechanisms. For their inhibitory effect need nucleoside analogues, such as 2'- deoxyadenosine, cell-specific co- pyrophosphate inhibitor. Their inhibitory potency, is surpassed by the pyrophosphate - independent nucleotide analogs, such as 2 ', 5'- dideoxyadenosine -3'- tetraphosphate, 2', 5'- dideoxyadenosine -3' -triphosphate. In addition, the adenylyl cyclases may be competitively inhibited by analogues of nucleotide substrate, such as β -L- 2 ', 3' -dideoxy- 5'- adenosine triphosphate, by displacement of the substrate ATP.

Swell

• Lyase
• Protein group