Guanosine pools

Ribavirin is a synthetic guanosine analogue that possesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza, RS V, HCV, HIV-1, and various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism of action has not been fully elucidated however, it appears to inhibit the synthesis of viral mRNA through an effect on nucleotide pools. Following absorption, host cell enzymes convert ribavirin to its monophosphate, diphosphate, and triphosphate forms. Ribavirin monophosphate... 

Fig. 8. Consensus sequences of arginine aptamers. (a) Sequence derived from a pool containing 25 random sequence positions Connell et al. [38], (b) This sequence binds to both arginine and guanosine [39], (c) 30 positions Tao and Frankel [40], (d) 74 random positions, partially random pool Famulok et al. [41]. (e) 113 random positions Geiger et al. [42].

Figure 2. Release of S-HT and guanosine (plus metabolites) fiom [ C]S-HT and [ C]-guanosine labeled storage and metabolic pools of platelets respectively in human PRP. Reproduced with pemiission publication of Agatwal, KC Ref. 8).

Receptor-mediated, guanosine 5 -triphosphate (GTP) protein-dependent signal transduction, initiated by stimulation of cholinergic M, receptors or dopaminergic D2 receptors, can activate PLAi to release arachidonate and/or docosahexaenoate from the sn-2 position of phospholipids (Axelrod et al., 1988 DeGeorge et al., 1991 Jones, Aral, Bell, Rapoport, 1996 Jones, Aral, Rapoport, 1997). This is illustrated for arachidonate in Fig. 4, which also shows that unlabeled arachidonic acid that is liberated by PI. A, into the brain unesterified pool can be rapidly labeled by tracer arachidonate injected into plasma (Grange et al., 1995 Washizaki et al., 1994). A fraction of the unesterified... 

Until 2001, it was thought that the mechanism of action of ribavirin involved a decrease in cellular guanosine triphosphate (GTP) pools resulting from inhibition of inosine monophosphate dehydrogenase by ribavirin monophosphate. More recently, the mechanism of action for ribavirin has been expanded to include lethal mutagenesis of the viral genome as a result of ribavirin triphosphate utilization by the error-prone viral RNA-dependent RNA polymerase, and incorporation of ribavirin into viral RNA. 

Mycophenolic acid (6-(4 hydroxy-6-methoxy-7-methyl-3-HDxo-5- pathalanyl)-4-methyl-4-hexenoic acid) also shown to inhibit IMP dehydrogenase (9) effectively interferred with the synthesis of guanosine nucleotides from IMP by PRBC (Table 1). The decrease (85%) in labelled GTP and total guanylates was significant (p <. 001). There was also a moderate (p <. 01) decrease in the concentration of GTP and in the level of the guanylate pool. 

Recently, the control of the increase in growth rate following amino acid upshift was studied in Bacillus subtilis. The GTP pools were manipulated by using mycophenolic acid, an inhibitor of guanine nucleotide biosynthesis, and by guanosine supplementation. It was found that an increase in GTP levels was required to obtain the growth rate increase on amino acid upshift (92). 

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