Editing Cyclic nucleotide

{{Short description|Cyclic nucleic acid}}
[[Image:Cyclic-adenosine-monophosphate-2D-skeletal.png|thumb|[[Cyclic adenosine monophosphate]].  The cyclic portion refers to the two single bonds between the [[phosphate]] group and the [[ribose]]]]

A '''cyclic nucleotide''' (cNMP) is a single-[[phosphate]] [[nucleotide]] with a cyclic bond arrangement between the [[sugar]] and phosphate groups.  Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a [[nitrogenous base]], and a single phosphate group.  As can be seen in the [[cyclic adenosine monophosphate]] (cAMP) and [[cyclic guanosine monophosphate]] (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' [[hydroxyl]] groups of the sugar, very often a [[ribose]].

Their biological significance includes a broad range of [[protein]]-[[ligand (biochemistry)|ligand]] interactions.  They have been identified as [[secondary messenger]]s in both [[hormone]] and [[ion channel|ion-channel]] signalling in [[eukaryote|eukaryotic]] cells, as well as [[allosteric effector]] compounds of [[DNA]] binding proteins in [[prokaryote|prokaryotic]] cells.  cAMP and cGMP are currently the most well documented cyclic nucleotides, however there is evidence that [[Cyclic CMP|cCMP]] (with [[cytosine]]) is also involved in eukaryotic cellular messaging.  The role of cyclic uridine monophosphate (cUMP) is even less well known.

Discovery of cyclic nucleotides has contributed greatly to the understanding of [[kinase]] and [[phosphatase]] mechanisms, as well as protein regulation in general.  Although more than 50 years have passed since their initial discovery, interest in cyclic nucleotides and their biochemical and physiological significance continues.

==History==
The understanding of the concept of second messengers, and in particular the role of cyclic nucleotides and their ability to relay physiological signals to a [[cell (biology)|cell]], has its origins in the research of [[glycogen]] metabolism by [[Carl Ferdinand Cori|Carl]] and [[Gerty Cori]], for which they were awarded a [[Nobel Prize in Physiology or Medicine]] in 1947.<ref name=beavo />  A number of incremental but important discoveries through the 1950s added to their research, primarily focusing on the activity of [[glycogen phosphorylase]] in dog [[liver]].  Glycogen phosphorylase catalyzes the first step in [[glycogenolysis]], the process of breaking [[glycogen]] into its substituent [[glucose]] parts.<ref name=newton />  [[Earl Wilbur Sutherland, Jr.|Earl Sutherland]] investigated the effect of the hormones [[epinephrine|adrenaline]] and [[glucagon]] on glycogen phosphorylase, earning him the Nobel Prize in Physiology or Medicine in 1971.<ref name=beavo />

In 1956 [[Edwin G. Krebs|Edwin Krebs]] and [[Edmond H. Fischer|Edmond Fischer]] discovered that [[adenosine triphosphate]] (ATP) is required for the conversion of [[phosphorylase|glycogen phosphorylase]] b to glycogen phosphorylase a. While investigating the action of adrenaline on [[glycogenolysis]] the next year, Sutherland and Walter Wosilait reported that inorganic phosphate is released when the [[enzyme substrate (biology)|enzyme]] liver phosphorylase is inactivated; but when it is activated, it incorporates a phosphate.<ref name=beavo /> The “active factor” that the hormones produced<ref name=newton />  was finally purified in 1958, and then identified as containing a [[ribose]], a phosphate, and an [[adenine]] in equal ratios. Further, it was proved that this factor reverted to 5’-AMP when it was inactivated.<ref name=beavo />

Evgeny Fesenko, Stanislav Kolesnikov, and Arkady Lyubarsky discovered in 1985 that [[cyclic guanosine monophosphate]] (cGMP) can initiate the photoresponse in [[rod cell|rods]]. Soon after, the role of cNMP in gated ion channels of chemosensitive [[cilium|cilia]] of [[olfactory sensory neuron]]s was reported by Tadashi Nakamura and Geoffrey Gold. In 1992 Lawrence Haynes and King-Wai Yau uncovered cNMP’s role in the light-dependent cyclic-nucleotide-gated channel of [[cone cell|cone photoreceptors]].<ref name=kaupp /> By the end of the decade, the presence of two types of intramembrane receptors was understood: Rs (which stimulates [[cyclase]]) and Ri (which inhibits cyclase).  Wei-Jen Tang and James Hurley reported in 1998 that adenylyl cyclase, which synthesizes cAMP, is regulated not only by [[hormone]]s and [[neurotransmitter]]s, but also by [[phosphorylation]], [[calcium]], [[forskolin]], and guanine nucleotide-binding proteins ([[G proteins]]).<ref name=newton />

==Chemistry of cNMPs==

===Structure===
[[Image:CGMP.png|thumb|[[Cyclic guanosine monophosphate]].  The cyclic portion refers to the two single bonds between the [[phosphate]] group and the [[ribose]]]]
The two most well-studied cyclic nucleotides are cyclic AMP (cAMP) and cyclic GMP (cGMP), while cyclic CMP (cCMP) and cyclic UMP (cUMP) are less understood.  cAMP is 3’5’-cyclic adenosine monophosphate, cGMP is 3’5’-cyclic guanosine monophosphate, cCMP is cytidine 3',5'-monophosphate, and cUMP is uridine 3',5'-cyclic phosphate.<ref>{{Cite journal|last=Seifert |first= R.|year=2015 |title=cCMP and cUMP: emerging second messengers |journal= Trends in Biochemical Sciences |volume= 40|issue= 1 |pages= 8–15 |url= https://doi.org/10.1016/j.tibs.2014.10.008 |doi=10.1016/j.tibs.2014.10.008|pmid= 25435399}}
</ref><ref name="Gomelsky">{{cite journal|last=Gomelsky|first=Mark|title=cAMP, c-di-GMP, c-di-AMP, and now cGMP: bacteria use them all!|doi=10.1111/j.1365-2958.2010.07514.x|pmid=21255104|volume=79|issue=3|journal=Molecular Microbiology|pages=562–565|pmc=3079424|year=2011}}</ref>

Each cyclic nucleotide has three components. It contains a nitrogenous base (meaning it contains nitrogen): for example, [[adenine]] in cAMP and [[guanine]] in cGMP. It also contains a sugar, specifically the five-[[carbon]] ribose. And finally, a cyclic nucleotide contains a phosphate.  A double-ring [[purine]] is the nitrogenous base for cAMP and cGMP, while cytosine, [[thymine]], and [[uracil]] each have a single-ring nitrogenous base ([[pyrimidine]]).

These three components are connected so that the nitrogenous base is attached to the first carbon of ribose (1’ carbon), and the phosphate group is attached to the 5’ carbon of ribose. While all nucleotides have this structure, the phosphate group makes a second connection to the ribose ring at the 3’ carbon in cyclic nucleotides.  Because the phosphate group has two separate bonds to the ribose sugar, it forms a cyclic ring.<ref>{{cite book|last=Nelson|first=David|title=Lehninger Principles of Biochemistry|year=2008|publisher=W.H. Freeman and Company|location=New York, NY|isbn=978-0-7167-7108-1|edition=Fifth|author2=Michael Cox|url-access=registration|url=https://archive.org/details/lehningerprincip00lehn_1}}</ref>

The [[atom]] numbering convention is used to identify the carbons and nitrogens within a cyclic nucleotide.  In the pentose, the carbon closest to the [[carbonyl]] group is labeled C-1.  When a pentose is connected to a nitrogenous base, carbon atom numbering is distinguished with a prime (') notation, which differentiates these carbons from the atom numbering of the nitrogenous base.<ref>{{cite web|title=Nucleotide Numbering|url=http://www.tulane.edu/~biochem/nolan/lectures/rna/frames/nucs.htm|publisher=Tulane University|access-date=9 May 2013}}</ref>

Therefore, for cAMP, 3’5’-cyclic adenosine monophosphate indicates that a single phosphate group forms a cyclic structure with the ribose group at its 3’ and 5’ carbons, while the ribose group is also attached to adenosine (this bond is understood to be at the 1’ position of the ribose).

==Biochemistry==
Cyclic nucleotides are found in both prokaryotic and eukaryotic cells.  Control of intracellular concentrations is maintained through a series of enzymatic reactions involving several families of proteins.  In higher order mammals, cNMPs are present in many types of tissue.

===Synthesis and Degradation===
[[File:Cyclic nucleotide synthesis.png|thumb|Generic cyclic nucleotide biosynthesis reaction by cyclase]]
Cyclic nucleotides are produced from the generic reaction NTP → cNMP + PP<sub>i</sub>,<ref name="camp">{{cite web |url=https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Adenylate+cyclase |title=National Library of Medicine - Medical Subject Headings, Adenylyl Cyclase }}</ref> where N represents a nitrogenous base.  The reaction is catalyzed by specific nucleotidyl cyclases, such that production of cAMP is catalyzed by [[adenylyl cyclase]] and production of cGMP is catalyzed by [[guanylyl cyclase]].<ref name="newton">{{cite journal |vauthors=Newton RP, Smith CJ |title=Cyclic nucleotides |journal=Phytochemistry |volume=65 |issue=17 |pages=2423–37 |date=September 2004 |pmid=15381406 |doi=10.1016/j.phytochem.2004.07.026 }}</ref>  [[Adenylyl cyclase]] has been found in both a transmembrane and [[cytosol]]ic form, representing distinct protein classes and different sources of cAMP.<ref name="Flacke">{{cite journal |vauthors=Flacke JP, Flacke H, Appukuttan A |title=Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells |journal=J. Biol. Chem. |volume=288 |issue=5 |pages=3126–35 |date=February 2013 |pmid=23255611 |doi=10.1074/jbc.M112.403279 |display-authors=etal |pmc=3561535|doi-access=free }}</ref>
[[File:Hydrolisis of 3' cNMP phosphodiester bond by phosphodiesterase.png|thumb|Generic hydrolysis reaction of 3' cNMP phosphodiester bond by phosphodiesterase]]
Both cAMP and cGMP are degraded by [[hydrolysis]] of the 3' [[phosphodiester bond]], resulting in a 5'NMP.  Degradation is carried out primarily by a class of enzymes known as [[phosphodiesterase]]s (PDEs).  In mammalian cells, there are 11 known PDE families with varying [[Protein isoform|isoforms]] of each protein expressed based on the cell's regulatory needs.  Some phosphodiesterases are cNMP-specific, while others can hydrolyze non-specifically.<ref name="bender">{{cite journal |vauthors=Bender AT, Beavo JA |s2cid=7397281 |title=Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use |journal=Pharmacol. Rev. |volume=58 |issue=3 |pages=488–520 |date=September 2006 |pmid=16968949 |doi=10.1124/pr.58.3.5 }}</ref> However, the cAMP and cGMP degradation pathways are much more understood than those for either cCMP or cUMP.  The identification of specific PDEs for cCMP and cUMP has not been as thoroughly established.<ref name="reineke">{{cite journal |vauthors=Reinecke D, Schwede F, Genieser HG, Seifert R |title=Analysis of substrate specificity and kinetics of cyclic nucleotide phosphodiesterases with N'-methylanthraniloyl-substituted purine and pyrimidine 3',5'-cyclic nucleotides by fluorescence spectrometry |journal=PLOS ONE |volume=8 |issue=1 |pages=e54158 |year=2013 |pmid=23342095 |pmc=3544816 |doi=10.1371/journal.pone.0054158 |bibcode=2013PLoSO...854158R |doi-access=free }}</ref>

===Target Binding===
Cyclic nucleotides can be found in many different types of eukaryotic cells, including photo-receptor rods and cones, [[smooth muscle cells]] and [[liver cells]].  Cellular concentrations of cyclic nucleotides can be very low, in the 10<sup>−7</sup>[[molar concentration|M]] range, because [[metabolism]] and function are often localized in particular parts of the cell.<ref name="beavo">{{cite journal |vauthors=Beavo JA, Brunton LL |title=Cyclic nucleotide research -- still expanding after half a century |journal=Nat. Rev. Mol. Cell Biol. |volume=3 |issue=9 |pages=710–8 |date=September 2002 |pmid=12209131 |doi=10.1038/nrm911 |s2cid=33021271 }}</ref>  A highly conserved [[cyclic nucleotide-binding domain]] (CNB) is present in all proteins that bind cNMPs, regardless of their biological function.  The domain consists of a beta sandwich architecture, with the cyclic nucleotide binding pocket between the [[beta sheet]]s.  The binding of cNMP causes a conformational change that affects the protein's activity.<ref name="rehmann">{{cite journal |vauthors=Rehmann H, Wittinghofer A, Bos JL |title=Capturing cyclic nucleotides in action: snapshots from crystallographic studies |journal=Nat. Rev. Mol. Cell Biol. |volume=8 |issue=1 |pages=63–73 |date=January 2007 |pmid=17183361 |doi=10.1038/nrm2082 |s2cid=7216248 }}</ref>  There is also data to support a synergistic binding effect amongst multiple cyclic nucleotides, with cCMP lowering the effective concentration (EC<sub>50</sub>) of cAMP for activation of [[protein kinase A]] (PKA).<ref name="wolter">{{cite journal |vauthors=Wolter S, Golombek M, Seifert R |title=Differential activation of cAMP- and cGMP-dependent protein kinases by cyclic purine and pyrimidine nucleotides |journal=Biochem. Biophys. Res. Commun. |volume=415 |issue=4 |pages=563–6 |date=December 2011 |pmid=22074826 |doi=10.1016/j.bbrc.2011.10.093 }}</ref>

==Biology==
Cyclic nucleotides are integral to a communication system that acts within cells.<ref name=beavo />  They act as "second messengers" by relaying the signals of many first messengers, such as hormones and neurotransmitters, to their physiological destinations. Cyclic nucleotides participate in many physiological responses,<ref name=bridges /> including receptor-effector coupling, down-regulation of drug responsiveness, protein-kinase cascades, and transmembrane signal transduction.<ref name=beavo />

Cyclic nucleotides act as second messengers when first messengers, which cannot enter the cell, instead bind to receptors in the cellular membrane.  The receptor changes conformation and transmits a signal that activates an enzyme in the cell membrane interior called adenylyl cyclase.  This releases cAMP into the cell interior, where it stimulates a protein kinase called cyclic AMP-dependent protein kinase.  By phosphorylating proteins, cyclic AMP-dependent protein kinase alters protein activity.  cAMP's role in this process terminates upon hydrolysis to AMP by phosphodiesterase.<ref name=newton />

{| class="wikitable" style="margin: 1em auto 1em auto;border-collapse:collapse"
|-
! Cyclic nucleotide !! Known binding proteins !! Pathway/Biological association
|-
| cAMP || 
# [[protein kinase A]] 
# cyclic nucleotide-gated ion channels 
# Epac
# [[Catabolite Activator Protein]] (CAP)
|| 
# smooth muscle relaxation<ref name="eckly">{{cite journal |vauthors=Eckly-Michel A, Martin V, Lugnier C |title=Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation |journal=Br. J. Pharmacol. |volume=122 |issue=1 |pages=158–64 |date=September 1997 |pmid=9298542 |pmc=1564898 |doi=10.1038/sj.bjp.0701339 }}</ref>
# photo/olfactory receptors<ref name="kaupp" />
# glucagon production in pancreatic [[beta cell]]s<ref name="holz">{{cite journal |author=Holz GG |title=Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell |journal=Diabetes |volume=53 |issue=1 |pages=5–13 |date=January 2004 |pmid=14693691 |pmc=3012130 |doi= 10.2337/diabetes.53.1.5}}</ref>
# [[lac operon]] regulation in [[Escherichia coli|E. coli]]<ref name="zhou">{{cite journal |author=Zhou Y, Zhang X, [[Richard H. Ebright|Ebright]] RH |title=Identification of the activating region of catabolite gene activator protein (CAP): isolation and characterization of mutants of CAP specifically defective in transcription activation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=13 |pages=6081–5 |date=July 1993 |pmid=8392187 |pmc=46871 |doi= 10.1073/pnas.90.13.6081|bibcode=1993PNAS...90.6081Z |doi-access=free }}</ref><ref name="meiklejohn">{{cite journal |vauthors=Meiklejohn AL, Gralla JD |title=Entry of RNA polymerase at the lac promoter |journal=Cell |volume=43 |issue=3 Pt 2 |pages=769–76 |date=December 1985 |pmid=3907860 |doi= 10.1016/0092-8674(85)90250-8|doi-access=free }}</ref>
|-
| cGMP || 
# [[cGMP-dependent protein kinase]] (PKG)
# cyclic nucleotide-gated ion channels 
|| 
# smooth muscle relaxation<ref name="eckly" />
# photo/olfactory receptors<ref name="kaupp">{{cite journal |vauthors=Kaupp UB, Seifert R |title=Cyclic nucleotide-gated ion channels |journal=Physiol. Rev. |volume=82 |issue=3 |pages=769–824 |date=July 2002 |pmid=12087135 |doi=10.1152/physrev.00008.2002 |citeseerx=10.1.1.319.7608 }}</ref>
|-
| cCMP 
|| 
# cGMP kinase I
# [[protein kinase A]] 
|| 
# smooth muscle relaxation<ref name="wolter" /><ref name="desch">{{cite journal |vauthors=Desch M, Schinner E, Kees F, Hofmann F, Seifert R, Schlossmann J |title=Cyclic cytidine 3',5'-monophosphate (cCMP) signals via cGMP kinase I |journal=FEBS Lett. |volume=584 |issue=18 |pages=3979–84 |date=September 2010 |pmid=20691687 |doi=10.1016/j.febslet.2010.07.059 |doi-access=free }}</ref>
|}

Cyclic nucleotides are well-suited to act as second messengers for several reasons. Their synthesis is energetically favorable, and they are derived from common metabolic components (ATP and GTP). When they break down into AMP/GMP and inorganic phosphate, these components are non-toxic.<ref name=bridges>{{cite journal|last=Bridges|first=D|author2=Fraser ME |author3=Moorhead GB |title=Cyclic nucleotide binding proteins in the Arabidopsis thaliana and Oryza sativa genomes|journal=BMC Bioinformatics|year=2005|volume=6|doi=10.1186/1471-2105-6-6|pmid=15644130|pages=6|pmc=545951|doi-access=free}}<!--|accessdate=2 April 2013--></ref> Finally, cyclic nucleotides can be distinguished from non-cyclic nucleotides because they are smaller and less [[chemical polarity|polar]].<ref name=newton />

===Biological significance===
The involvement of cyclic nucleotides on biological functions is varied, while an understanding of their role continues to grow. There are several examples of their biological influence. They are associated with long-term and short-term memory.<ref>{{cite book|last=Beavo|first=Joseph|title=Cyclic Nucleotide Phosphodiesterases in Health and Disease|url=https://archive.org/details/cyclicnucleotide00beav|url-access=limited|year=2010|publisher=CRC Press|location=Boca Raton, FL|isbn=9780849396687|page=[https://archive.org/details/cyclicnucleotide00beav/page/n560 546]|author2=Sharron Francis |author3=Miles Houslay }}</ref>  They also work in the liver to coordinate various enzymes that control [[blood sugar|blood glucose]] and other [[nutrient]]s.<ref name=Sutherland>{{cite journal|last=Sutherland|first=Earl|author2=Robison GA |author3=Butcher RW |title=Some aspects of the biological role of adenosine 3',5'-monophosphate (cyclic AMP)|journal=Circulation|year=1968|volume=37|issue=2|pages=279–306|doi=10.1161/01.CIR.37.2.279|doi-access=free}}<!--|accessdate=23 April 2013--></ref> In [[bacteria]], cyclic nucleotides bind to catabolite gene activator protein (CAP), which acts to increase metabolic enzymatic activity by increasing the rate of [[DNA]] [[transcription (genetics)|transcription]].<ref name="Gomelsky"/> They also facilitate relaxation of smooth muscle cells in [[Blood vessel|vascular]] tissue,<ref name=lincoln>{{cite journal|last=Lincoln|first=TM|author2=Cornwell TL|title=Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation|journal=Blood Vessels|year=1991|volume=28|issue=1–3|pages=129–37|pmid=1848122|doi=10.1159/000158852}}</ref> and activate cyclic CNG channels in [[retina]]l photoreceptors and [[olfactory sensory neuron]]s. In addition, they potentially activate cyclic CNG channels in: [[pineal gland]] light sensitivity, sensory neurons of the [[vomeronasal organ]] (which is involved in the detection of [[pheromone]]s), [[taste receptor]] cells, [[cell signaling|cellular signaling]] in [[sperm]], airway [[epithelium|epithelial]] cells, [[gonadotropin-releasing hormone]] (GnRH)-secreting [[neuron]]al cell line, and [[kidney|renal]] [[collecting duct system|inner medullary collecting duct]].<ref name=kaupp />

===Pathway mutations and related diseases===
Examples of disruptions of cNMP pathways include: mutations in CNG channel [[gene]]s are associated with degeneration of the retina and with [[color blindness]];<ref name=kaupp /> and [[gene expression|overexpression]] of cytosolic or [[soluble adenylyl cyclase]] (sAC) has been linked to human [[prostate cancer|prostate carcinoma]].  Inhibition of sAC, or knockdown by [[RNA interference]] (RNAi) [[transfection]] has been shown to prevent the [[cell growth|proliferation]] of the prostate carcinoma cells.  The regulatory pathway appears to be part of the EPAC pathway and not the PKA pathway.<ref name="Flacke" />

Phosphodiesterases, principle regulators of cNMP degradation, are often targets for therapeutics.  Caffeine is a known PDE inhibitor, while drugs used for the treatment of erectile dysfunction like [[sildenafil]] and [[tadalafil]] also act through inhibiting the activity of phosphodiesterases.<ref name="bender" />

==References==
{{Reflist}}

==External links==
* {{MeshName|Nucleotides,+Cyclic}}

{{Nucleobases, nucleosides, and nucleotides}}

[[Category:Nucleotides]]
[[Category:Cyclic nucleotides| ]]