Циклдық нуклеотидтер: құрылымы, қасиеттері және биологиялық маңызы

Cyclic nucleic acid

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 interactions. 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. cAMP and cGMP are currently the most well documented cyclic nucleotides, however there is evidence that 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.

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, has its origins in the research of glycogen metabolism by Carl and Gerty Cori, for which they were awarded a Nobel Prize in Physiology or Medicine in 1947. 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. 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. 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, 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. Adenylyl cyclase has been found in both a transmembrane and cytosolic form, representing distinct protein classes and different sources of cAMP. 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. 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.

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 often localized in particular parts of the cell. 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 sheets. The binding of cNMP causes a conformational change that affects the protein's activity. 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 of protein kinase A (PKA).

Examples of disruptions of cNMP pathways include: mutations in CNG channel genes are associated with degeneration of the retina and with color blindness; 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. 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.