ADENYLATE CYCLASE: CHARACTERISTICS, TYPES, FUNCTIONS - BIOLOGY - 2025

The adenylate cyclase or adenylyl cyclase is the enzyme responsible for conversion of ATP, a molecule of high energy in cyclic AMP, an important signaling molecule which activates various proteins cyclic AMP-dependent with important physiological functions.

Its activity is controlled by various factors such as, for example, the concerted action of hormones, neurotransmitters and other regulatory molecules of different nature (divalent calcium ions and G proteins, to name a few).

Adenylate cyclase diagram (Source: User Bensaccount on en.wikipedia via Wikimedia Commons)

The main importance of this enzyme lies in the importance of the product of the reaction that it catalyzes, cyclic AMP, since it participates in the control of many cellular phenomena related to metabolism and development, as well as the response to different external stimuli.

In nature, both unicellular organisms (relatively simple) and large and complex multicellular animals use cyclic AMP as a second messenger, and therefore the enzymes that produce it.

Phylogenetic studies establish that these enzymes are derived from a common ancestor prior to the separation of eubacteria and eukaryotes, suggesting that cyclic AMP had different functions, perhaps related to ATP production.

It is possible to accept such a statement, since the reaction catalyzed by adenylate cyclase is easily reversible, which can be seen in the equilibrium constant for ATP synthesis (K eq ≈ 2.1 ± 0.2 10 -9 M 2).

Characteristics and structure

Most eukaryotic adenylate cyclase enzymes are associated with the plasma membrane, but in bacteria and mammalian sperm cells they are found as soluble proteins in the cytosol.

In yeast and some bacteria they are peripheral membrane proteins, while in certain amoeba species they are molecules with a single transmembrane segment.

Structural characteristics

They are proteins composed of large polypeptide chains (of more than 1,000 amino acid residues), which cross the plasma membrane 12 times through two regions composed of six transmembrane domains of alpha helix conformation.

Each transmembrane region is separated by a large cytosolic domain, which is responsible for catalytic activity.

Among eukaryotic organisms there are some conserved motifs in a fragment of the amino terminal region of these enzymes, as well as a cytoplasmic domain of around 40 kDa, which is delimited by the hydrophobic sections.

Catalytic site

The reaction that these enzymes catalyze, that is, the formation of a diester bond through a nucleophilic attack of the OH group in position 3 'to the phosphate group of the nucleoside triphosphate in position 5', depends on a common structural motif known as the domain Palm".

This "palm" domain is composed of a "βαβααβ" motif ("β" meaning the β-folded sheets and "α" the alpha helices) and has two invariable aspartic acid residues that coordinate the two responsible metal ions catalysis, which can be divalent magnesium or zinc ions.

Many studies related to the quaternary structure of these enzymes have revealed that their catalytic unit exists as a dimer whose formation depends on the transmembrane segments, which join in the endoplasmic reticulum during the formation of the protein.

Location

It has been determined that like many integral membrane proteins, such as G proteins, those with phosphatidylinositol anchors, and many others, adenyl cyclases are found in special membrane regions or micro domains known as "lipid rafts" (from English "lipid raft").

These membrane domains can be up to hundreds of nanometers in diameter and are composed mainly of cholesterol and sphingolipids with long, predominantly saturated fatty acid chains, which makes them less fluid and allows the accommodation of transmembrane segments of different proteins.

Adenylate cyclases have also been found associated with subregions of lipid rafts known as "caveolae" (from English "caveolae"), which are rather invaginations of the membrane rich in cholesterol and a protein associated with this called caveolin.

Types

In nature, there are three well-defined classes of adenylate cyclase and two that are currently the subject of discussion.

- Class I: they are present in many Gram-negative bacteria such as E. coli, for example, where the cyclic AMP product of the reaction has functions as a ligand for transcription factors responsible for the regulation of catabolic operons.

- Class II: found in some pathogens of bacterial genera such as Bacillus or Bordetella, where they serve as extracellular toxins. They are proteins activated by host calmodulin (absent in bacteria).

- Class III: known as the "universal" class and are phylogenetically related to guanylate cyclases, which perform similar functions. They are found in both prokaryotes and eukaryotes, where they are regulated by different pathways.

Mammalian adenylate cyclases

In mammals, at least nine types of these enzymes have been cloned and described, encoded by nine independent genes and belonging to adenyl cyclase class III.

They share complex structures and membrane topologies, as well as the duplicated catalytic domains that are characteristic of them.

For mammals, the nomenclature used to refer to isoforms corresponds to the letters AC (for adenylate cyclase) and a number from 1 to 9 (AC1 - AC9). Two variants of the AC8 enzyme have also been reported.

The isoforms present in these animals are homologous with respect to the sequence of the primary structure of their catalytic sites and the three-dimensional structure. The inclusion of one of these enzymes within each "type" is mainly related to the regulatory mechanisms that operate on each isoform.

They have patterns of expression that are often tissue-specific. All isoforms can be found in the brain, although some are restricted to specific areas of the central nervous system.

Features

The main function of the enzymes belonging to the Adenylate Cyclase family is to transform ATP into cyclic AMP and for this they catalyze the formation of an intramolecular 3'-5 'diester bond (reaction similar to that catalyzed by DNA polymerases). with the release of a pyrophosphate molecule.

In mammals, the different variants that can be achieved have been related to cell proliferation, ethanol dependence, synaptic plasticity, drug dependence, circadian rhythm, olfactory stimulation, learning and memory.

Some authors have suggested that adenylate cyclases may have an additional function as transporter molecules or, what is the same, channel proteins and ionic transporters.

However, these hypotheses have only been tested based on the arrangement or topology of the transmembrane segments of these enzymes, which share some homologies or structural similarities (but not sequence) with certain ion transport channels.

Both cyclic AMP and PPi (pyrophosphate), which are the products of the reaction, have functions at the cellular level; but their importance depends on the organism where they are.

Regulation

The great structural diversity among adenyl cyclases demonstrates a great susceptibility to multiple forms of regulation, which allows them to integrate into a wide variety of cellular signaling pathways.

The catalytic activity of some of these enzymes depends on alpha ketoacids, while others have much more complex regulatory mechanisms involving regulatory subunits (by stimulation or inhibition) that depend, for example, on calcium and other generally soluble factors, as well as of other proteins.

Many adenylate cyclases are negatively regulated by subunits of some G proteins (inhibit their function), while others exert more activating effects.

References

1. Cooper, DMF (2003). Regulation and organization of adenylyl cyclases and cAMP. Biochemical Journal, 375, 517-529.
2. Cooper, D., Mons, N., & Karpen, J. (1995). Adenylyl cyclases and the interaction between calcium and cAMP signaling. Nature, 374, 421-424.
3. Danchin, A. (1993). Phylogeny of Adenylyl Cyclases. Advances in Second Messenger and Phosphoprotein Research, 27, 109–135.
4. Hanoune, J., & Defer, N. (2001). Regulation and Role of Adenylyl Cyclase Isoforms. Ann. Rev. Pharmacol. Toxicol., 41, 145-174.
5. Linder, U., & Schultz, JE (2003). The class III adenylyl cyclases: multi-purpose signaling modules. Cellular Signaling, 15, 1081-1089.
6. Tang, W., & Gilman, AG (1992). Adenylyl Cyclases. Cell, 70, 669-672.