Nucleotide kinase, action

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

There are several mechanisms involved in the vasodilator effect of flavonoids. The main mechanism seems to be related to the inhibition of protein kinase C or some of the processes activated by this protein. The inhibition of other protein kinases and cyclic nucleotide phosphodiesterase activity and blockage of calcium entry can also contribute to this effect to a greater or lesser extent (Alvarez Castro and Orallo, 2003 Herrera and others 1996). Certain flavonoids, like the flavonol myricetin, have a two-phase action on blood vessels vasoconstrictor in lowest active concentrations and vasodilator in higher concentrations (Alvarez Castro and Orallo, 2003). 

Figure 14.10 Diagrammatic representation of regulation of the opening of an ion channel by phosphoiylation of a protein in the channel. The neurotransmitter-receptor complex functions as a nucleotide exchange factor to activate a G-protein which then activates a protein kinase. This is identical to control of G-proteins in the action of hormones (Chapter 12, see Figure 12.21). Phosphorylation of a protein in the ion channel opens it to allow movement of Na+ ions. The formation of the complex, activation of the G-protein and the kinase takes place on the postsynaptic membrane. An example of the structural organisation and the involvement of a G-protein is shown in Chapter 12 (Figure 12.6).

The purine and pyrimidine bases can be converted to then-respective nncleotides by reaction with 5-phosphoribosyl 1-pyrophosphate. Since these bases are not very soluble, they are not transported in the blood, so that the reactions are only of qnantitative significance in the intestine, where the bases are produced by degradation of nucleotides. In contrast, in some cells, nucleosides are converted back to nucleotides by the activity of kinase enzymes. In particular, adenosine is converted to AMP, by the action of adenosine kinase, and uridine is converted to UMP by a uridine kinase... 

This protein kinase (known as protein kinase A or PK-A) has an R2C2 quaternary structure that binds 3, 5 -cAMP at its dimeric regulatory (R) subunit with resultant release of two catalytic (C) subunits. The free energy of hydrolysis of the cychc nucleotide activator is large (AG 13 kcal/mol) and allows the 3, 5 -cAMP to be virtually irreversibly converted to AMP by the action of a specific phosphodiesterase. This protein kinase, originally discovered by the Nobelists Edwin Krebs and Edward Fischer, is now considered to be the prototype for over two thousand members of the protein kinase superfamily. 

The energy charge quotient has a value of unity (or, 1.00) when only ATP is present and a value of zero when only AMP is present. Thus, the adenine nucleotide system is said to be fully charged at EC = 1 and fully discharged at EC = 0. At intermediate values, the adenine nucleotides are interconverted by adenylate kinase, and their concentrations are constrained by the adenylate kinase mass action ratio ... 

Mechanism of action. Several mechanisms have been proposed for the vasodilator effects of flavonoids including inhibition of A) PKC, B) Ca2+ entry, C) cyclic nucleotide PDEs and D) tyrosin kinases. 

In conclusion, flavonoids exert endothelium-independent vasodilator effects in isolated vascular smooth muscles that are related to the structure of the compound tested. The main vasodilator mechanism of flavonoids seems to be related to the inhibition of PKC, although an inhibitory effect on cyclic nucleotide PDEs and Ca2+ uptake and other protein kinases may also contribute to these actions, Fig. (4). 

Antiviral actions of purine and pyrimidine analogs. Acyclovir and ganciclovir (top) are phosphorylated first by viral kinase to the monophosphate. This intermediate and the drugs shown on the left are then phosphorylated by host cell kinases to the nucleotide analogs that inhibit viral replication. (Modified and reproduced, with permission, from Trevor AT, Katzung BG, Masters SM Pharmacology Examination Board Review, 6th ed. McGraw-Hill, 2002.)... 

Gemcitabine is phosphorylated initially by the enzyme deoxycytidine kinase and then by other nucleoside kinases to the di- and triphosphate nucleotide forms, which then inhibit DNA synthesis. Inhibition is considered to result from two actions inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA and incorporation of gemcitabine triphosphate into DNA. Following incorporation of gemcitabine nucleotide, only one additional nucleotide can be added to the growing DNA strand, resulting in chain termination. 

Francis SH, Corbin JD (1999) Cyclic nucleotide-dependent protein kinases intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci 36 275-328... 

Mode of action Like acyclovir, ganciclovir is activated through conversion to the nucleoside triphosphate by viral and cellular enzymes, the actual pathway depending on the virus. Cytomegalovirus is deficient in thymidine kinase, and therefore forms the triphosphate by another route. The nucleotide competitively inhibits viral DNA polymerase and can be incorporated into the DNA to decrease the rate of chain elongation. 

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