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=Cyclic Nucleotides=
 * 1) Basic introduction text
 * Cyclic nucleotides are single phosphate nucleotides 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.  Their ring-like bond consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.


 * To date, their biological signifcance includes a broad range of protein-ligand interaction. They have been identified as secondary messengers in both hormone and ion-channel signalling in eukaryotic cells, as well as allosteric effector compounds of DNA binding proteins in prokaryotic cells.    Cyclcic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are currently the most well documented cyclic nucleotides, however there is evidence that cCMP (cytosine) is also involved in eukaryotic cellular messaging.  The discovery of cyclic nucleotides has contributed greatly to our understanding of kinase and phosphatase mechanisms, as well as protein regulation in general.  It has been more than 50 years since cAMP was discovered as a secondary messenger for adrenaline, and the role of cyclic nucleotides in cellular pathways continues to expand.

=Chemistry of cNMPs=

Structure
The two most well-studied cyclic nucleotides are cyclic AMP (cAMP) and cyclic GMP (cGMP). cAMP is 3’5’-cyclic adenosine monophosphate, while cGMP is 3’5’-cyclic guanosine monophosphate.

Each cyclic nucleotide has three components: 1) a nitrogenous base (meaning it contains nitrogen), adenine in the case of cAMP and guanine in the case of cGMP); 2) a sugar, specifically ribose, which is a pentose (containing five carbons); and 3) a phosphate. The nitrogenous base for cAMP and cGMP is a double-ring purine. A single-ring nitrogenous base (pyrimidine) is the structure for the other nitrogenous bases, cytosine, thymine, and uracil.

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 this structure is true for all nucleotides, cyclic nucleotides have the added significance of the phosphate group making a second connection to the ribose ring at the 3’ carbon. Because the phosphate group has two separate bonds to the ribose sugar, it forms a cyclic ring.

Additional Chemical Information
The atom numbering convention identifies the carbons and nitrogens (for cyclic nucleotides). The carbons of the pentose is such that 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.

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=

Synthesis and Degradation
Cyclic nucleotides are produced from the generic reaction NTP → NMP + PPi, 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. 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 phosphodiesterases, also known as PDE's. However the cAMP an cGMP degradation pathways are much more understood than those for either cCMP or cUMP.

Cellular Distribution
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 10-7M range, because metabolism and function are restricted to distinct subcellular compartments. Even though Many of the proteins have very different biological functions, they all have a conserved cyclic nucleotide binding domain (CNB). The domain consists a beta sandwich architecture, with the cyclic nucleotide binding pocket between the beta sheets. The binding of cNMP causes a conformational change that affects the proteins activity.

=Biology= The signals of many first messengers, such as hormones and neurotransmitters, are relayed to their physiological destinations via second messengers. This communication system acts within cells (intracellularly) with cyclic nucleotides carrying out this functionality. These second messengers are involved in numerous physiological responsesbridges to include transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades, and down-regulation of drug responsiveness.

The function of cyclic nucleotides as second messengers begins when first messengers, which cannot enter the cell, instead bind to receptors in the cellular membrane. This causes the receptor to change conformation. This change in shape results in the receptor transmitting a signal, activating an enzyme in the cell membrane interior called adenylyl cyclase. This causes cAMP to synthesize and release into the cell interior, where it stimulates a protein kinase called cyclic AMP-dependent protein kinase. This protein kinase then alters protein activity by phosphorylating these proteins. The activity of cAMP is then terminated when phosphodiesterase hydrolyzes cAMP to produce AMP.

Cyclic nucleotides are well-suited to act as second messengers for several reasons:
 * They are derived from common metabolic components (ATP and GTP)
 * Their synthesis is energetically favorable
 * They form non-toxic products when broken down into AMP and GMP and inorganic phosphate
 * They can be identified from non-cyclic nucleotides because their structure renders them smaller and less polar

Biological Significance
While an understanding of the involvement of cyclic nucleotides on biological functions continues to grow, it is varied and in some cases, still tenuous. Examples of their biological influence:


 * They are associated with long-term and short-term memory
 * They work in the liver to coordinate various enzymes that control blood glucose and other nutrients
 * In bacteria, they bind to catabolite gene activator protein (CAP), which acts to increase metabolic enzymatic activity by increasing the rate of DNA transcription
 * They facilitate relaxation of smooth muscle cells in vascular tissue
 * They activate cyclic CNG channels in retinal photoreceptors and olfactory sensory neurons
 * They potentially activate cyclic CNG channels in:
 * Pineal gland light sensitivity
 * Sensory neurons of the vomeronasal organ, which is involved in the detection of pheromones
 * Taste receptor cells
 * Cellular signaling in sperm
 * Airway epithelial cells
 * Gonadotropin-releasing hormone-secreting neuronal cell line
 * Renal inner medullary collecting duct

Pathway Mutations
Examples of disruptions of cNMP pathways include:


 * Mutations in CNG channel genes are associated with degeneration of the retina and with color blindness

=History= The understanding of the concept of second messengers, and in particular the role of cyclic nucleotides, has its origins in the research of glycogen metabolism by Carl and Gerty Cori, for which they were awarded a Nobel Prize in 1947. A number of incremental but important discoveries through the 1950s added to their research, primarily focused on studies of glycogen phosphorylase activity in dog liver and how it is influenced by the hormones adrenaline and glucagon, with Earl Sutherland himself earning the Nobel Prize for Medicine in 1971 for his work in this area. Each of these historical milestones began to elucidate a puzzle that culminated in the understanding that cAMP relays physiological signals to a cell:


 * 1956: Krebs and Fischer discovered that the reaction in which phosphorylase B converts to phosphorylase A requires ATP
 * 1957:
 * Sutherland and Wosilait, while investigating the actin of adrenaline on glycogenolysis, discovered that when the enzyme liver phosphorylase is inactivated, inorganic phosphate is released.
 * Rall, Sutherland, and Wosilait reported that when liver phosphorylase is activated, it incorporates a phosphate.
 * 1958: The “active factor” that the hormones produced was finally purified, and identified as containing a ribose, a phosphate, and an adenine in equal ratios. Further, they proved that when this factor was inactivated, it reverted to 5’-AMP.
 * 1985: Fesenko et al discovered that cGMP activates the light-dependent cyclic-nucleotide-gated channel of rods.
 * 1987: Nakamura and Gold discovered the role of cNMP in gated ion channels of chemosensitive cilia of olfactory sensory neurons.
 * 1990: Beavo and Houslay document that phosphodiesterase has many isoforms from several phosphodiesterase families, differing in specificity, kinetics, and distribution.
 * 1992: Haynes and Yau discovered cNMP’s role in the light-dependent cyclic-nucleotide-gated channel of cone photoreceptors.
 * 1994: Strader reports that there are two types of intramembrane receptors: Rs (which stimulates cyclase) and Ri (which inhibits cyclase). The path through the cellular membrane is also much more complicated than once through.
 * 1998: Tang and Hurley document that cyclase responds not just to neurotransmitters and hormones, but also to other inputs such as calcium, aluminum fluoride and forskolin, toxins such as cholera, and phosphorylation.