Editing Adenylyl cyclase (section)

== Classes ==

=== Class I ===
{{Infobox protein family|Name=Adenylate cyclase, class-I|Symbol=Adenylate_cycl|InterPro=IPR000274|Pfam=PF01295|PROSITE=PDOC00837}}
The first class of adenylyl cyclases occur in many bacteria including ''E. coli'' (as CyaA {{UniProt|P00936}} [unrelated to the Class II enzyme]).<ref name=":2" /> 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 [[cAMP receptor protein|CRP]], also known as CAP. Class I AC's are large cytosolic enzymes (~100&nbsp;kDa) with a large regulatory domain (~50&nbsp;kDa) that indirectly senses glucose levels. {{as of|2012}}, 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<sup>2+</sup> ions. S103, S113, D114, D116 and W118 are the five absolutely essential residues. The class I catalytic domain ({{Pfam|PF12633}}) belongs to the same superfamily ({{Pfam|CL0260}}) as the palm domain of [[DNA polymerase beta]] ({{Pfam|PF18765}}). Aligning its sequence onto the structure onto a related archaeal [[CCA tRNA nucleotidyltransferase]] ({{PDB|1R89}}) allows for assignment of the residues to specific functions: [[Adenosine triphosphate|γ-phosphate]] binding, structural stabilization, DxD motif for metal ion binding, and finally ribose binding.<ref>{{cite journal | vauthors = Linder JU | title = Structure-function relationships in Escherichia coli adenylate cyclase | journal = The Biochemical Journal | volume = 415 | issue = 3 | pages = 449–454 | date = November 2008 | pmid = 18620542 | doi = 10.1042/BJ20080350 }} ([https://pastebin.com/JHJeQuJn alignment])</ref>

=== Class II ===
These adenylyl cyclases are toxins secreted by pathogenic bacteria such as ''Bacillus anthracis'', ''Bordetella pertussis'', ''Pseudomonas aeruginosa'', and ''Vibrio vulnificus'' during infections.<ref>{{cite journal | vauthors = Ahuja N, Kumar P, Bhatnagar R | title = The adenylate cyclase toxins | journal = Critical Reviews in Microbiology | volume = 30 | issue = 3 | pages = 187–196 | date = 2004 | pmid = 15490970 | doi = 10.1080/10408410490468795 | s2cid = 23893594 | author-link1 = Nita Ahuja }}</ref> 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]], one of which is [[anthrax toxin]]. Several crystal structures are known for AC-II enzymes.<ref>{{cite journal | vauthors = Khanppnavar B, Datta S | title = Crystal structure and substrate specificity of ExoY, a unique T3SS mediated secreted nucleotidyl cyclase toxin from Pseudomonas aeruginosa | journal = Biochimica et Biophysica Acta (BBA) - General Subjects| volume = 1862 | issue = 9 | pages = 2090–2103 | date = September 2018 | pmid = 29859257 | doi = 10.1016/j.bbagen.2018.05.021 | s2cid = 44151852 }}</ref><ref>{{cite journal | vauthors = Guo Q, Shen Y, Lee YS, Gibbs CS, Mrksich M, Tang WJ | title = Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin | journal = The EMBO Journal | volume = 24 | issue = 18 | pages = 3190–3201 | date = September 2005 | pmid = 16138079 | pmc = 1224690 | doi = 10.1038/sj.emboj.7600800 }}</ref><ref>{{cite journal | vauthors = Drum CL, Yan SZ, Bard J, Shen YQ, Lu D, Soelaiman S, Grabarek Z, Bohm A, Tang WJ | display-authors = 6 | title = Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin | journal = Nature | volume = 415 | issue = 6870 | pages = 396–402 | date = January 2002 | pmid = 11807546 | doi = 10.1038/415396a | s2cid = 773562 | bibcode = 2002Natur.415..396D }}</ref>

=== Class III ===
{{Infobox protein family
|Name=Adenylyl cyclase class-3/guanylyl cyclase
|Symbol=Guanylate_cyc
|Pfam=PF00211
|Pfam_clan=CL0276
|InterPro=IPR001054
|PROSITE=PS50125
|SMART=SM00044
|SCOP=1tl7
|TCDB=8.A.85
|OPM family= 546
|OPM protein=6r3q
}}
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]] signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ([[cytoplasm]]). 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]] to [[cyclic adenosine monophosphate]] (cAMP). cAMP is known as a [[second messenger]].<ref name="Campbell">{{cite book | vauthors = Reece J, Campbell N | title = Biology | publisher = Benjamin Cummings | location = San Francisco | year = 2002 | pages = [https://archive.org/details/biologyc00camp/page/207 207] | isbn = 978-0-8053-6624-2 | url-access = registration | url = https://archive.org/details/biologyc00camp/page/207 }}</ref>

[[Cyclic AMP]] is an important molecule in [[eukaryote|eukaryotic]] [[signal transduction]], a so-called [[second messenger]]. Adenylyl cyclases are often activated or inhibited by [[G protein]]s, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli.<ref name=":3">{{cite journal | vauthors = Hanoune J, Defer N | title = Regulation and role of adenylyl cyclase isoforms | journal = Annual Review of Pharmacology and Toxicology | volume = 41 | issue = 1 | pages = 145–174 | date = April 2001 | pmid = 11264454 | doi = 10.1146/annurev.pharmtox.41.1.145 }}</ref> 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]] and [[HCN channel|cyclic nucleotide-gated ion channels]].<ref name=":3" />

[[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.<ref name="pmid17128267">{{cite journal | vauthors = Schröder-Lang S, Schwärzel M, Seifert R, Strünker T, Kateriya S, Looser J, Watanabe M, Kaupp UB, Hegemann P, Nagel G | display-authors = 6 | title = Fast manipulation of cellular cAMP level by light in vivo | journal = Nature Methods | volume = 4 | issue = 1 | pages = 39–42 | date = January 2007 | pmid = 17128267 | doi = 10.1038/nmeth975 | s2cid = 10616442 | url = http://edoc.hu-berlin.de/18452/10021 }}</ref> A green-light activated rhodopsin adenylyl cyclase (CaRhAC) has recently been engineered by modifying the nucleotide binding pocket of rhodopsin [[guanylyl cyclase]].

==== Structure ====
[[Image:Adenylyl cyclase.png|thumb|Structure of adenylyl cyclase]]
Most class III adenylyl cyclases are transmembrane [[protein]]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.<ref name="pmid14575863">{{cite journal | vauthors = Linder JU, Schultz JE | title = The class III adenylyl cyclases: multi-purpose signalling modules | journal = Cellular Signalling | volume = 15 | issue = 12 | pages = 1081–1089 | date = December 2003 | pmid = 14575863 | doi = 10.1016/s0898-6568(03)00130-x }}</ref>

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.<ref name="pmid14575863"/>{{rp|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.<ref name="pmid14575863"/>

==== Types ====
There are ten known isoforms of adenylyl cyclases in [[mammal]]s:
{{Columns-list|colwidth=30em|
* [[ADCY1]]
* [[ADCY2]]
* [[ADCY3]]
* [[ADCY4]]
* [[ADCY5]]
* [[ADCY6]]
* [[ADCY7]]
* [[ADCY8]]
* [[ADCY9]]
* [[ADCY10]]
}}
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.<ref name=":0" /><ref name=":1" /><ref name=":2" /> Adenylyl cyclase activity is controlled by heterotrimeric G proteins.<ref name=":0" /><ref name=":1" /><ref name=":2" /> The inactive or inhibitory form exists when the complex consists of alpha, beta, and gamma subunits, with GDP bound to the alpha subunit.<ref name=":0" /><ref name=":2" /> In order to become active, a ligand must bind to the receptor and cause a conformational change.<ref name=":0" /> This conformational change causes the alpha subunit to dissociate from the complex and become bound to GTP.<ref name=":0" /> This G-alpha-GTP complex then binds to adenylyl cyclase and causes activation and the release of cAMP.<ref name=":0" /> 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.<ref name=":0" /> 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.<ref name=":0" /> It is also regulated by [[forskolin]],<ref name=":3" /> as well as other isoform-specific effectors:

* Isoforms I, III, and VIII are also stimulated by [[calcium|Ca<sup>2+</sup>]]/[[calmodulin]].<ref name=":3" />
* Isoforms V and VI are inhibited by Ca<sup>2+</sup> in a calmodulin-independent manner.<ref name=":3" />
* Isoforms II, IV and IX are stimulated by alpha subunit of the G protein.<ref name=":3" />
* Isoforms I, V and VI are most clearly inhibited by Gi, while other isoforms show less dual regulation by the inhibitory G protein.<ref name=":3" />
* [[Soluble adenylyl cyclase|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]], forms local cAMP signalling domains.<ref name="pmid24324443">{{cite journal | vauthors = Rahman N, Buck J, Levin LR | title = pH sensing via bicarbonate-regulated "soluble" adenylyl cyclase (sAC) | journal = Frontiers in Physiology | volume = 4 | pages = 343 | date = November 2013 | pmid = 24324443 | pmc = 3838963 | doi = 10.3389/fphys.2013.00343 | doi-access = free }}</ref>

In [[neuron]]s, calcium-sensitive adenylyl cyclases are located next to calcium [[ion channel]]s for faster reaction to Ca<sup>2+</sup> 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.<ref name=":4">{{cite journal | vauthors = Hogan DA, Muhlschlegel FA | title = Candida albicans developmental regulation: adenylyl cyclase as a coincidence detector of parallel signals | journal = Current Opinion in Microbiology | volume = 14 | issue = 6 | pages = 682–686 | date = December 2011 | pmid = 22014725 | doi = 10.1016/j.mib.2011.09.014 }}</ref>  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.<ref>{{cite journal | vauthors = Ostrom KF, LaVigne JE, Brust TF, Seifert R, Dessauer CW, Watts VJ, Ostrom RS | title = Physiological roles of mammalian transmembrane adenylyl cyclase isoforms | journal = Physiological Reviews | volume = 102 | issue = 2 | pages = 815–857 | date = April 2022 | pmid = 34698552 | pmc = 8759965 | doi = 10.1152/physrev.00013.2021 }}</ref> Soluble adenylyl cyclase (sAC, AC10) has a critical role in sperm motility.<ref>{{cite journal | vauthors = Esposito G, Jaiswal BS, Xie F, Krajnc-Franken MA, Robben TJ, Strik AM, Kuil C, Philipsen RL, van Duin M, Conti M, Gossen JA | display-authors = 6 | title = Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 9 | pages = 2993–2998 | date = March 2004 | pmid = 14976244 | pmc = 365733 | doi = 10.1073/pnas.0400050101 | bibcode = 2004PNAS..101.2993E | doi-access = free }}</ref> Adenylyl cyclase has been implicated in memory formation, functioning as a [[Coincidence detection in neurobiology|coincidence detector]].<ref name=":3" /><ref name=":4" /><ref>{{cite journal | vauthors = Willoughby D, Cooper DM | title = Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains | journal = Physiological Reviews | volume = 87 | issue = 3 | pages = 965–1010 | date = July 2007 | pmid = 17615394 | doi = 10.1152/physrev.00049.2006 | citeseerx = 10.1.1.336.3746 }}</ref><ref>{{cite journal | vauthors = Mons N, Guillou JL, Jaffard R | title = The role of Ca2+/calmodulin-stimulable adenylyl cyclases as molecular coincidence detectors in memory formation | journal = Cellular and Molecular Life Sciences | volume = 55 | issue = 4 | pages = 525–533 | date = April 1999 | pmid = 10357223 | doi = 10.1007/s000180050311 | s2cid = 10849274 | pmc = 11147090 }}</ref><ref>{{cite journal | vauthors = Neve KA, Seamans JK, Trantham-Davidson H | title = Dopamine receptor signaling | journal = Journal of Receptor and Signal Transduction Research | volume = 24 | issue = 3 | pages = 165–205 | date = August 2004 | pmid = 15521361 | doi = 10.1081/RRS-200029981 | s2cid = 12407397 | citeseerx = 10.1.1.465.5011 }}</ref>

=== Class IV ===
{{redirect|CyaB|the airport with code CYAB|Arctic Bay Airport}}
{{Anchor|Adenylyl cyclase CyaB|CyaB}}
{{Infobox protein family
|InterPro=IPR008173
|Name=Adenylyl cyclase CyaB
|Symbol=CyaB
|CDD=cd07890
|SCOP=2ACA
|CATH=1YEM
}}
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}}).<ref>{{cite journal | vauthors = Gallagher DT, Smith NN, Kim SK, Heroux A, Robinson H, Reddy PT | title = Structure of the class IV adenylyl cyclase reveals a novel fold | journal = Journal of Molecular Biology | volume = 362 | issue = 1 | pages = 114–122 | date = September 2006 | pmid = 16905149 | doi = 10.1016/j.jmb.2006.07.008 }}</ref> AC-IV forms a superfamily with mammalian [[thiamine-triphosphatase]] called CYTH (CyaB, thiamine triphosphatase).<ref>{{cite journal | vauthors = Kohn G, Delvaux D, Lakaye B, Servais AC, Scholer G, Fillet M, Elias B, Derochette JM, Crommen J, Wins P, Bettendorff L | display-authors = 6 | title = High inorganic triphosphatase activities in bacteria and mammalian cells: identification of the enzymes involved | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e43879 | date = 2012 | pmid = 22984449 | pmc = 3440374 | doi = 10.1371/journal.pone.0043879 | doi-access = free | bibcode = 2012PLoSO...743879K }}</ref>

=== Classes V and VI ===
{{Infobox protein family
|Name=AC Class VI (DUF3095)
|Symbol=DUF3095
|Pfam=PF11294
|InterPro=IPR021445
|below=[http://gremlin.bakerlab.org/sub.php?id=1557471140 contact prediction]
}}
These forms of AC have been reported in specific bacteria (''[[Prevotella]] ruminicola'' {{UniProt|O68902}} and ''[[Rhizobium]] etli'' {{UniProt|Q8KY20}}, respectively) and have not been extensively characterized.<ref>{{cite journal | vauthors = Cotta MA, Whitehead TR, Wheeler MB | title = Identification of a novel adenylate cyclase in the ruminal anaerobe, Prevotella ruminicola D31d | journal = FEMS Microbiology Letters | volume = 164 | issue = 2 | pages = 257–260 | date = July 1998 | pmid = 9682474 | doi = 10.1111/j.1574-6968.1998.tb13095.x | doi-access = free }} GenBank [https://www.ncbi.nlm.nih.gov/nuccore/AF056932 AF056932].</ref> 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.<ref>{{cite journal | vauthors = Téllez-Sosa J, Soberón N, Vega-Segura A, Torres-Márquez ME, Cevallos MA | title = The Rhizobium etli cyaC product: characterization of a novel adenylate cyclase class | journal = Journal of Bacteriology | volume = 184 | issue = 13 | pages = 3560–3568 | date = July 2002 | pmid = 12057950 | pmc = 135151 | doi = 10.1128/jb.184.13.3560-3568.2002 }} GenBank [https://www.ncbi.nlm.nih.gov/nuccore/AF299113 AF299113].</ref>