Inosinate dehydrogenase mechanism

Respiratory syncytial vims (RSV) is a major cause of mortality in yoimg infants and the elderly. The mechanism of action of ribavirin is not entirely clear although it is probable that it acts as an inhibitor of inosine dehydrogenase which is involved in the introduction of a carbonyl group into the inosine stmcture en route to the synthesis of gua-nosine triphosphate (GTP). GTP is required for viral RNA transcription. Ribavirin may also interfere with the action of the viral RNA polymerase. There is some debate over the effectiveness of ribavirin in treating RSV. It is also used in combination with interferon in the treatment of hepatitis C. RSV is also treated with monoclonal antibody therapy and this is discussed in the Chapter 26. 

Human type II inosine monophosphate dehydrogenase catalyses NAD-dependent conversion of inosine monophosphate (IMP) into xanthosine monophosphate (XMP) measurements of the primary kinetic isotope effect using [ H]IMP suggest that both substrates (IMP and NAD) can dissociate from the enzyme-substrate complex therefore, the kinetic mechanism is not ordered. NMR studies indicate hydride transfer to the B or pro-S face of the nicotinamide ring of NAD, while kinetic studies suggest... 

Mechanism of Action An immunologic agent that suppresses the immunologically mediated inflammatory response by inhibiting inosine monophosphate dehydrogenase, an enzyme that deprives lymphocytes of nucleotides necessary for DNA and RNA synthesis, thus inhibiting the proliferation of T and B lymphocytes. Therapeutic Effect Prevents transplant rejection. 

Mechanism of Action Selectively inhibits inosine monophosphate dehydrogenase in the de novo pathway of purine synthesis, producing potent cytostatic effects on T and B lymphocytes... 

In the second control mechanism, exerted at a later stage, an excess of GMP in the cell inhibits formation of xanthylate from inosinate by IMP dehydrogenase, without affecting the formation of AMP (Fig. 22-35). Conversely, an accumulation of adenylate inhibits formation of adenylosuccinate by adenylosuccinate synthetase, without affecting the biosynthesis of GMP. In the third mechanism, GTP is required in the conversion of IMP to AMP (Fig. 22-34, step (T)), whereas ATP is required for conversion of IMP to GMP (step (4)), a reciprocal arrangement that tends to balance the synthesis of the two ribonucleotides. 

Mechanism of Action. Mycophenolate mofetil inhibits a specific enzyme (inosine monophosphate dehydrogenase) that is responsible for the synthesis of DNA precursors in T and B lymphocytes.39 50 Because these lymphocytes cannot synthesize adequate amounts of DNA, their ability to replicate and proliferate is impaired, thus blunting the immune response. This drug may also inhibit lymphocyte attraction and adhesion to the vascular endothelium, thereby impairing the lymphocytes ability to migrate to the site of the foreign (transplanted) tissues and to infiltrate from the bloodstream into these tissues.50... 

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. 

MECHANISMS OE ACTION AND RESISTANCE Ribavirin alters cellular nucleotide pools and inhibits viral mRNA synthesis. Intracellular phosphorylation to the mono-, di-, and triphosphate derivatives is mediated by host cell enzymes. In both uninfected and RSV-infected cells, the predominant derivative is the triphosphate, which has an intracellular of <2 hours. Ribavirin monophosphate competitively inhibits cellular inosine-5 -phosphate dehydrogenase and interferes with the synthesis of GTP and thus nucleic acid synthesis. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5 capping of viral messenger RNA and specifically influenza virus transcriptase activity. Ribavirin has multiple sites of action, and some of these e.g., inhibition of GTP synthesis) may potentiate others e.g., inhibition of GTP-dependent enzymes). Ribavirin also may enhance viral mutagenesis such that some viruses may be inhibited in effective replication, so-caUed lethal mutagenesis. 

Mechanism of action This drug is rapidly converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of purine synthesis. This action suppresses both B and T lymphocyte activation. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for purine synthesis. 

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