Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:ATP = 3′,5′-cyclic AMP + diphosphate
It has key regulatory roles in essentially all
cells.
It is the most
polyphyletic
A polyphyletic group is an assemblage of organisms or other evolving elements that is of mixed evolutionary origin. The term is often applied to groups that share similar features known as homoplasies, which are explained as a result of conver ...
known
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
: six distinct classes have been described, all
catalyzing the same reaction but representing unrelated
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
families
Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Ideal ...
with no known
sequence or structural homology.
The best known class of adenylyl cyclases is class III or AC-III (Roman numerals are used for classes). AC-III occurs widely in
eukaryotes and has important roles in many human
tissues.
All classes of adenylyl cyclase
catalyse
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the conversion of
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...
(ATP) to
3',5'-cyclic AMP (cAMP) and
pyrophosphate
In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...
.
Magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s are generally required and appear to be closely involved in the enzymatic mechanism. The cAMP produced by AC then serves as a regulatory signal via specific cAMP-binding
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s, either
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s, enzymes (e.g., cAMP-dependent
kinases), or ion
transporters.
Classes
Class I
The first class of adenylyl cyclases occur in many bacteria including ''E. coli'' (as CyaA
nrelated to the Class II enzyme.
This was the first class of AC to be characterized. It was observed that ''E. coli'' deprived of glucose produce cAMP that serves as an internal signal to activate expression of genes for importing and metabolizing other sugars. cAMP exerts this effect by binding the transcription factor
CRP, also known as CAP. Class I AC's are large cytosolic enzymes (~100 kDa) with a large regulatory domain (~50 kDa) that indirectly senses glucose levels. , no crystal structure is available for class I AC.
Some indirect structural information is available for this class. It is known that the N-terminal half is the catalytic portion, and that it requires two Mg
2+ ions. S103, S113, D114, D116 and W118 are the five absolutely essential residues. The class I catalytic domain () belongs to the same superfamily () as the palm domain of
DNA polymerase beta
DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the ''POLB'' gene.
Function
In eukaryotic cells, DNA polymerase beta (POLB) performs base excision repair (BER) required for DNA mainte ...
(). Aligning its sequence onto the structure onto a related archaeal
CCA tRNA nucleotidyltransferase
CCA tRNA nucleotidyltransferase (, ''CCA-adding enzyme'', ''tRNA adenylyltransferase'', ''tRNA CCA-pyrophosphorylase'', ''tRNA-nucleotidyltransferase'', ''transfer-RNA nucleotidyltransferase'', ''transfer ribonucleic acid nucleotidyl transferase'', ...
() allows for assignment of the residues to specific functions:
γ-phosphate binding, structural stabilization, DxD motif for metal ion binding, and finally ribose binding.
Class II
These adenylyl cyclases are toxins secreted by pathogenic bacteria such as ''Bacillus anthracis'', ''Bordetella pertussis'', ''Pseudomonas aeruginosa'', and ''Vibrio vulnificus'' during infections. These bacteria also secrete proteins that enable the AC-II to enter host cells, where the exogenous AC activity undermines normal cellular processes. The genes for Class II ACs are known as
cyaA
Adenylate cyclase toxin (CyaA) is released from bacterium Bordetella pertussis by the T1SS (Type 1 secretion system) and released in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense.
CyaA ...
, one of which is
anthrax toxin
Anthrax toxin is a three-protein exotoxin secreted by virulent strains of the bacterium, '' Bacillus anthracis''—the causative agent of anthrax. The toxin was first discovered by Harry Smith in 1954. Anthrax toxin is composed of a cell-bind ...
. Several crystal structures are known for AC-II enzymes.
Class III
These adenylyl cyclases are the most familiar based on extensive study due to their important roles in human health. They are also found in some bacteria, notably ''
Mycobacterium tuberculosis'' where they appear to have a key role in pathogenesis. Most AC-III's are integral membrane proteins involved in transducing extracellular signals into intracellular responses. A Nobel Prize was awarded to
Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the "fight or flight" response. The effect of adrenaline is via a
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...
signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylyl cyclase, which transmits a signal by converting
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...
to
cyclic adenosine monophosphate
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP). cAMP is known as a
second messenger.
Cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...
is an important molecule in
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
signal transduction, a so-called
second messenger. Adenylyl cyclases are often activated or inhibited by
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...
s, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli.
Following activation of adenylyl cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
and
cyclic nucleotide-gated ion channels.
Photoactivated adenylyl cyclase (PAC) was discovered in ''
Euglena gracilis'' and can be expressed in other organisms through genetic manipulation. Shining blue light on a cell containing PAC activates it and abruptly increases the rate of conversion of ATP to cAMP. This is a useful technique for researchers in neuroscience because it allows them to quickly increase the intracellular cAMP levels in particular neurons, and to study the effect of that increase in neural activity on the behavior of the organism.
A green-light activated rhodopsin adenylyl cyclase (CaRhAC) has recently been engineered by modifying the nucleotide binding pocket of rhodopsin
guanylyl cyclase
Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
.
Structure
Most class III adenylyl cyclases are transmembrane
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s 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.
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.
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.
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.
Adenylyl cyclase activity is controlled by heterotrimeric G proteins.
The inactive or inhibitory form exists when the complex consists of alpha, beta, and gamma subunits, with GDP bound to the alpha subunit.
In order to become active, a ligand must bind to the receptor and cause a conformational change.
This conformational change causes the alpha subunit to dissociate from the complex and become bound to GTP.
This G-alpha-GTP complex then binds to adenylyl cyclase and causes activation and the release of cAMP.
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.
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.
It is also regulated by
forskolin
Forskolin (coleonol) is a labdane diterpene produced by the plant ''Coleus barbatus'' (Blue Spur Flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua. As with other members of the large diterpene class of ...
,
as well as other isoform-specific effectors:
* Isoforms I, III, and VIII are also stimulated by
Ca2+/
calmodulin.
* Isoforms V and VI are inhibited by Ca
2+ in a calmodulin-independent manner.
* Isoforms II, IV and IX are stimulated by alpha subunit of the G protein.
* Isoforms I, V and VI are most clearly inhibited by Gi, while other isoforms show less dual regulation by the inhibitory G protein.
*
Soluble AC (sAC) is not a transmembrane form and is not regulated by G proteins or forskolin, instead acts as a bicarbonate/pH sensor. It is anchored at various locations within the cell and, with
phosphodiesterases
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...
, forms local cAMP signalling domains.
In
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s, calcium-sensitive adenylyl cyclases are located next to calcium
ion channels for faster reaction to Ca
2+ 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.
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
Adenylyl cyclase has been implicated in memory formation, functioning as a
coincidence detector.
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 (). AC-IV forms a superfamily with mamallian
thiamine-triphosphatase called CYTH (CyaB, thiamine triphosphatase).
Classes V and VI
These forms of AC have been reported in specific bacteria (''
Prevotella
''Prevotella'' is a genus of Gram-negative bacteria.
''Prevotella'' spp. are members of the oral, vaginal, and gut microbiota and are often recovered from anaerobic infections of the respiratory tract. These infections include aspiration pn ...
ruminicola'' and ''
Rhizobium
''Rhizobium'' is a genus of Gram-negative soil bacteria that fix nitrogen. ''Rhizobium'' species form an endosymbiotic nitrogen-fixing association with roots of (primarily) legumes and other flowering plants.
The bacteria colonize plant cells ...
etli'' , respectively) and have not been extensively characterized. 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.
[ GenBan]
AF299113
Additional images
File:Beta adrenergic receptor kinase.JPG, Beta adrenergic receptor kinase
G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ''ADRBK1'' gene. GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfa ...
pathway
References
Further reading
*
External links
*
*Interactive 3D views of Adenylate cyclase at
{{DEFAULTSORT:Adenylyl Cyclase
EC 4.6.1
Cell signaling
Signal transduction