Cyclic nucleotide
A cyclic nucleotide (cNMP) is a single-
Their biological significance includes a broad range of
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
In 1956
Evgeny Fesenko, Stanislav Kolesnikov, and Arkady Lyubarsky discovered in 1985 that
Chemistry of cNMPs
Structure
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 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.[6]
The
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
Cyclic nucleotides are produced from the generic reaction NTP → cNMP + PPi,
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 (PDEs). In mammalian cells, there are 11 known PDE families with varying isoforms 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]
Target Binding
Cyclic nucleotides can be found in many different types of eukaryotic cells, including photo-receptor rods and cones,
Biology
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 less polar.[2]
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.
Examples of disruptions of cNMP pathways include: mutations in CNG channel genes are associated with degeneration of the retina and with color blindness;[3] and overexpression of cytosolic or soluble adenylyl cyclase (sAC) has been linked to human prostate carcinoma. Inhibition of sAC, or knockdown by RNA interference (RNAi) transfection has been shown to prevent the proliferation 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 like sildenafil and tadalafil also act through inhibiting the activity of phosphodiesterases.[10]
References
- ^ S2CID 33021271.
- ^ PMID 15381406.
- ^ PMID 12087135.
- PMID 25435399.
- ^ PMID 21255104.
- ISBN 978-0-7167-7108-1.
- ^ "Nucleotide Numbering". Tulane University. Retrieved 9 May 2013.
- ^ "National Library of Medicine - Medical Subject Headings, Adenylyl Cyclase".
- ^ PMID 23255611.
- ^ S2CID 7397281.
- PMID 23342095.
- S2CID 7216248.
- ^ PMID 22074826.
- ^ PMID 15644130.
- ^ PMID 9298542.
- PMID 14693691.
- PMID 8392187.)
{{cite journal}}
: CS1 maint: multiple names: authors list (link - PMID 3907860.
- PMID 20691687.
- ISBN 9780849396687.
- .
- PMID 1848122.
External links
- Nucleotides,+Cyclic at the U.S. National Library of Medicine Medical Subject Headings (MeSH)