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Derivatives of nucleic acids that control the activity of several proteins within cells to regulate and coordinate metabolism. They are members of a group of molecules known as intracellular second messengers; their levels are regulated by hormones and neurotransmitters, which are the extracellular first messengers in a regulatory pathway. Cyclic nucleotides are found naturally in all living cells.
Two major forms of cyclic nucleotides are characterized: 3′,5′-cyclic adenosine monophosphate (cyclic AMP or cAMP) and 3′,5′-cyclic guanosine monophosphate (cyclic GMP or cGMP). Like all nucleotides, cAMP and cGMP contain three functional groups: a nitrogenous aromatic base (adenine or guanine), a sugar (ribose), and a phosphate. Cyclic nucleotides differ from other nucleotides in that the phosphate group is linked to two different hydroxyl (3′ and 5′) groups of the ribose sugar and hence forms a cyclic ring. This cyclic conformation allows cAMP and cGMP to bind to proteins to which other nucleotides cannot.
An increase in cAMP or cGMP triggered by hormones and neurotransmitters can have many different effects on any individual cell. The type of effect is dependent to some extent on the cellular proteins to which the cyclic nucleotides may bind. Three types of effector proteins are able to bind cyclic nucleotides: protein kinases, ion channels, and cyclic nucleotide phosphodiesterases.
Protein kinases are enzymes which are able to transfer a phosphate group to (phosphorylate) individual amino acids of other proteins. This action often changes the function of the phosphorylated protein. Ion channels are proteins found in the outer plasma membrane of some cells; binding of cyclic nucleotides to them can alter the flow of sodium ions across the cell membranes. Cyclic nucleotide phosphodiesterases are enzymes responsible for the degradation of cyclic nucleotides.
In bacteria, cAMP can bind to a fourth type of protein, which can also bind to deoxyribonucleic acid (DNA). This catabolite gene activator protein (CAP) binds to specific bacterial DNA sequences, stimulating the rate at which DNA is copied into ribonucleic acid (RNA) and increasing the amount of key metabolic enzymes in the bacteria.
In humans, cyclic nucleotides acting as second messengers play a key role in many vital processes and some diseases. For example, in the brain, cAMP and possibly cGMP are critical in the formation of both long-term and short-term memory. In the liver, cAMP coordinates the function of many metabolic enzymes to control the level of glucose and other nutrients in the bloodstream. See Adenosine triphosphate (ATP), Enzyme, Nucleic acid, Nucleoprotein, Nucleotide, Protein
nucleotides in whose molecules the phosphoric-acid residue, bonded to the ribose carbon atoms in the 5’ and 3’ positions, forms a ring (seeNUCLEOTIDES); universal regulators of biochemical processes in living cells.
Cyclic 3’,5’-adenosine monophosphate (cyclic AMP), a white powder that is readily soluble in water, is the best studied cyclic nucleotide. It was discovered in 1957 by the American biochemist E. Sutherland and his co-workers during the study of the activation mechanism of the liver enzyme phosphorylase by the hormones glucagon and epinephrine.
In animal and human tissues, cyclic AMP serves as a mediator in the accomplishment of the multiple functions of different hormones and other biologically active compounds, such as certain mediators, toxins, and lactins. In bacteria, when easily assimilated compounds, such as glucose, are lacking in the environment, the content of cyclic AMP in the cell increases, which leads to the biosynthesis of adaptive, or induced, enzymes necessary for the assimilation of other sources of nutrition. The cyclic AMP level in the cells of Salmonella typhimurium determines the fate of a phage that has found its way into a cell; at high concentrations of cyclic AMP, lysogenization of the bacterial culture occurs, while at low concentrations, the phase induces lysis of the culture. In the myxomycete Dictyostelium discoideum, cyclic AMP acts as an attractant, drawing the individual cells to one another. In other plants, it mediates the effect of phytochrome on the synthesis of beta-cyonine pigments, for example, in Amaranthus paniculatus.
The concentration of cyclic AMP in mammalian tissues is very low, amounting to tenths of 1 micromole per kilogram of wet tissue (10–7–10–6 mole). Upon the activation of adenyl cyclase, or adenylate cyclase, which catalyzes the biosynthesis of cyclic AMP, or upon the blocking of phosphodiesterase, which accomplishes the hydrolysis of cyclic AMP, the concentration of cyclic AMP in the cell increases rapidly. Thus, the content of cyclic AMP in the cell is determined by the ratio of the activity of adenyl cyclase and phosphodiesterase.
The connection between a hormone or other chemical signal (first messenger) and cyclic AMP (second messenger) is established by the adenylyl cyclase complex, which includes a receptor, which is specific for a particular hormone or other biologically active compound and which is located on the outer side of the cell membrane, and by adenyl cyclase, which is located on the inner side of the membrane. The hormone, by reacting with the receptor, in many cases activates adenylyl cyclase, which catalyzes the biosynthesis of cyclic AMP. The concentration of cyclic AMP thus formed in the cell exceeds the concentration of the hormone acting on the cell by a factor of 100.
The basis of the mechanism of the action of cyclic AMP in animal and human tissues lies in its interaction with protein kinases—enzymes displaying activity in the presence of cyclic AMP (see Figure 1). The binding of cyclic AMP to the regulator subunit of protein kinase leads to the dissociation of the enzyme and activation of its catalytic subunit, which, freed from its regulator subunit, is capable of phosphorylating specific proteins, including enzymes. The change in the properties of these macro-molecules by phosphorylation also changes the corresponding cell function. For example, the action of epinephrine on liver cells is accompanied by the phosphorylation of two enzymes— phosphorylase and glycogen synthetase. Phosphorylase is thus activated, which leads to the rapid hydrolysis of glycogen, the storage substance of the liver. With the onset of glycogen hydrolysis, further synthesis of glycogen ceases, since the enzyme that participates in its formation, glycogen synthetase, loses its activity upon phosphorylation by protein kinase. The same hormone, acting through the cyclic AMP mediator, induces different functional responses in different tissues, depending on the features of the tissues.
In cases when an organism is under stress, when energy requirements are very high, the adrenal medulla forms the hormone epinephrine in increased amounts. In the liver, epinephrine causes the active splitting (phosphorolysis) of glycogen, the formation of phosphorus esters of glucose, and the introduction of large amounts of glucose into the blood. In fatty tissue, increased epinephrine leads to the hydrolysis of lipids. Upon reaching the heart, epinephrine increases the contractile strength of the heart muscle, increases blood circulation, and improves the nutrition of tissues by mobilizing all of the organism’s energy. Cyclic AMP also plays a role in the morphology, mobility, and pigmentation of cells, in hematopoiesis, in cell immunity, and in viral infections.
Some mediators, such as acetylcholine, may accelerate the formation of another cyclic nucleotide, 3’,5’-guanosine monophosphate (cyclic GMP), which is synthesized in the cell from guanosine triphosphate upon activation of the enzyme guanylate cyclase, component of the guanylate cyclase complex located in the cell membrane. Many effects of cyclic GMP are characteristically directly opposite the effects of cyclic AMP. The antagonistic relationship of the cyclic nucleotides is most evident in complex systems, when the diverse modification of many proteins is required to regulate cell function; this modification is accomplished by the coordinated action of alternately activated cyclic AMP-dependent and cyclic GMP-dependent protein kinases.
In bacteria, cyclic AMP, by combining with a nonenzyme receptor protein, adds to DNA and permits the enzyme RNA polymerase to initiate transcription of the gene responsible for the synthesis of an induced enzyme (seeOPERON). Thus, the mechanisms for the actions of cyclic AMP in bacteria and in animal and human tissues differ in principle.
The study of the role of cyclic nucleotides in living cells, one of the most rapidly developing disciplines in biochemistry, has already made significant contributions to the understanding of the mechanisms of biological regulation at the molecular level.
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Vasil’ev, V. Iu., N. N. Guliaev, and E. S. Severin. “Tsiklicheskii adenozinmonofosfat—biologicheskaia rol’ i mekhanizm deistviia.” Zhurnal Vsesoiuznogo khimicheskogo obshchestva im. D. I. Mendeleeva, 1975, vol. 20, no. 3.
Doman, N. G., and E. P. Fedenko. “Biologicheskaia rol’ tsiklicheskogo AMF.” Uspekhi biologicheskoi khimii, 1976, vol. 17.
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Advances in Cyclic Nucleotide Research, vols. 1–6. New York-Amsterdam, 1972–75.
E. P. FEDENKO