Acyclic nucleotide (cNMP) is a single-phosphatenucleotide with a cyclic bond arrangement between thesugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, anitrogenous base, and a single phosphate group. As can be seen in thecyclic adenosine monophosphate (cAMP) andcyclic 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 aribose.
Their biological significance includes a broad range ofprotein-ligand interactions. They have been identified assecondary messengers in bothhormone andion-channel signalling ineukaryotic cells, as well asallosteric effector compounds ofDNA binding proteins inprokaryotic cells. cAMP and cGMP are currently the most well documented cyclic nucleotides, however there is evidence thatcCMP (withcytosine) 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 ofkinase andphosphatase 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.
The understanding of the concept of second messengers, and in particular the role of cyclic nucleotides and their ability to relay physiological signals to acell, has its origins in the research ofglycogen metabolism byCarl andGerty Cori, for which they were awarded aNobel Prize in Physiology or Medicine in 1947.[1] A number of incremental but important discoveries through the 1950s added to their research, primarily focusing on the activity ofglycogen phosphorylase in dogliver. Glycogen phosphorylase catalyzes the first step inglycogenolysis, the process of breakingglycogen into its substituentglucose parts.[2]Earl Sutherland investigated the effect of the hormonesadrenaline andglucagon on glycogen phosphorylase, earning him the Nobel Prize in Physiology or Medicine in 1971.[1]
In 1956Edwin Krebs andEdmond Fischer discovered thatadenosine triphosphate (ATP) is required for the conversion ofglycogen phosphorylase b to glycogen phosphorylase a. While investigating the action of adrenaline onglycogenolysis the next year, Sutherland and Walter Wosilait reported that inorganic phosphate is released when theenzyme liver phosphorylase is inactivated; but when it is activated, it incorporates a phosphate.[1] The "active factor" that the hormones produced[2] was finally purified in 1958, and then identified as containing aribose, a phosphate, and anadenine in equal ratios. Further, it was proved that this factor reverted to 5'-AMP when it was inactivated.[1]
Evgeny Fesenko, Stanislav Kolesnikov, and Arkady Lyubarsky discovered in 1985 thatcyclic guanosine monophosphate (cGMP) can initiate the photoresponse inrods. Soon after, the role of cNMP in gated ion channels of chemosensitivecilia ofolfactory sensory neurons 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 ofcone photoreceptors.[3] By the end of the decade, the presence of two types of intramembrane receptors was understood: Rs (which stimulatescyclase) and Ri (which inhibits cyclase). Wei-Jen Tang and James Hurley reported in 1998 that adenylyl cyclase, which synthesizes cAMP, is regulated not only byhormones andneurotransmitters, but also byphosphorylation,calcium,forskolin, and guanine nucleotide-binding proteins (G proteins).[2]
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.[4][5]
Each cyclic nucleotide has three components. It contains a nitrogenous base (meaning it contains nitrogen): for example,adenine in cAMP andguanine in cGMP. It also contains a sugar, specifically the five-carbon ribose. And finally, a cyclic nucleotide contains a phosphate. A double-ringpurine is the nitrogenous base for cAMP and cGMP, while cytosine,thymine, anduracil 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.[6]
Theatom numbering convention is used to identify the carbons and nitrogens within a cyclic nucleotide. In the pentose, the carbon closest to thecarbonyl 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.[7]
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).
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.
Cyclic nucleotides are produced from the generic reaction NTP → cNMP + PPi,[8] where N represents a nitrogenous base. The reaction is catalyzed by specific nucleotidyl cyclases, such that production of cAMP is catalyzed byadenylyl cyclase and production of cGMP is catalyzed byguanylyl cyclase.[2]Adenylyl cyclase has been found in both a transmembrane andcytosolic form, representing distinct protein classes and different sources of cAMP.[9]
Both cAMP and cGMP are degraded byhydrolysis of the 3'phosphodiester bond, resulting in a 5'NMP. Degradation is carried out primarily by a class of enzymes known asphosphodiesterases (PDEs). In mammalian cells, there are 11 known PDE families with varyingisoforms of each protein expressed based on the cell's regulatory needs. Some phosphodiesterases are cNMP-specific, while others can hydrolyze non-specifically.[10] 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.[11]
Cyclic nucleotides can be found in many different types of eukaryotic cells, including photo-receptor rods and cones,smooth muscle cells andliver cells. Cellular concentrations of cyclic nucleotides can be very low, in the 10−7M range, becausemetabolism and function are often localized in particular parts of the cell.[1] A highly conservedcyclic 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 thebeta sheets. The binding of cNMP causes a conformational change that affects the protein's activity.[12] There is also data to support a synergistic binding effect amongst multiple cyclic nucleotides, with cCMP lowering the effective concentration (EC50) of cAMP for activation ofprotein kinase A (PKA).[13]
Cyclic nucleotides are integral to a communication system that acts within cells.[1] 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,[14] including receptor-effector coupling, down-regulation of drug responsiveness, protein-kinase cascades, and transmembrane signal transduction.[1]
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.[2]
| Cyclic nucleotide | Known binding proteins | Pathway/Biological association |
|---|---|---|
| cAMP |
|
|
| cGMP |
| |
| cCMP |
|
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.[14] Finally, cyclic nucleotides can be distinguished from non-cyclic nucleotides because they are smaller and lesspolar.[2]
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.[20] They also work in the liver to coordinate various enzymes that controlblood glucose and othernutrients.[21] Inbacteria, cyclic nucleotides bind to catabolite gene activator protein (CAP), which acts to increase metabolic enzymatic activity by increasing the rate ofDNAtranscription.[5] They also facilitate relaxation of smooth muscle cells invascular tissue,[22] and activate cyclic CNG channels inretinal photoreceptors andolfactory sensory neurons. In addition, they potentially activate cyclic CNG channels in:pineal gland light sensitivity, sensory neurons of thevomeronasal organ (which is involved in the detection ofpheromones),taste receptor cells,cellular signaling insperm, airwayepithelial cells,gonadotropin-releasing hormone (GnRH)-secretingneuronal cell line, andrenalinner medullary collecting duct.[3]
Examples of disruptions of cNMP pathways include: mutations in CNG channelgenes are associated with degeneration of the retina and withcolor blindness;[3] andoverexpression of cytosolic orsoluble adenylyl cyclase (sAC) has been linked to humanprostate carcinoma. Inhibition of sAC, or knockdown byRNA interference (RNAi)transfection has been shown to prevent theproliferation of the prostate carcinoma cells. The regulatory pathway appears to be part of the EPAC pathway and not the PKA pathway.[9]
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 likesildenafil andtadalafil also act through inhibiting the activity of phosphodiesterases.[10]
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