Inosine dehydrogenase

Ribavirin [4.15) is of special interest because of its broad spectrum of attack. It is active against both DNA and RNA viruses. Also known as tribavirin and Virazole , this substance is l-)8-D-ribofuranosyl-l,2,4-triazole-3-carboxamide. In vivo, it is changed to the 5 -monophosphate which inhibits inosinate dehydrogenase, and hence prevents the formation of guanylic acid on which synthesis of both DNA and RNA depend. It is being used clinically for the treatment of viral pneumonia and measles although the results are not quite clear-cut (Smith and Kirkpatrick, 1980). 

Bacterial, plant, and animal inosinate dehydrogenases require NAD+ as the electron acceptor, and either K+ or NH4+, as well as thiols, for maximum activity. 

The actual physiological role of these stimulatory and inhibitory effects of purine nucleotides on the enzymes of purine ribonucleoside interconversion is very difficult to assess, and little is knovm about the matter at the present time. Inhibition of inosinate dehydrogenase by metabolites of guanine (S6) and inhibition of guanylate reductase by metabolites of adenine (41) appear to occur in some bacteria supplied with these bases. 

Inosinate dehydrogenases from bacterial and mammalian sources are inhibited by ribonucleotides of 6-mercaptopurine and 6-thioguanine. Inosinate protects the enzyme against this inhibition, and its analogues are believed to react at the active site of the enzyme. The extents of inhibition by 6-thiopurines and 6-chloropurine are progressive with time,... 

C11H13N3O5 267.241 Potent inhibitor of inosinate dehydrogenase activity. Antineoplastic agent. Cryst. (EtOH). Mp 182-185°. 

The pathways for the formation of allopurinol-l-ribonucleotide (l-Alo-5 -P) and the two ribonucleotides of oxipurinol (l-0xi-5 -P and 7-Oxi-5 -P) are shown in Figure 1. The nucleotides required as standards for comparison with the metabolites of allopurinol were synthesized enz3miatically vitro from their respective bases, utilizing phosphoribosyltransferases from E. coli and beef erythrocytes [10]. The conversion of l-Alo-5 -P to l-0xi-5 -P did not occur with the inosinate dehydrogenase from Sarcoma 180 cells [9]. It is not known whether oxipurinol-7-riboside is a substrate for uridine kinase. 

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. 

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme of purine nucleotide biosynthesis. Proliferation of activated lymphocytes dq ends on rapid de novo production of purine nucleotides for DNA synthesis. 

Inosine 5 -Monophosphate Dehydrogenase. A series of 21 known inosine 5 -monophosphate dehydrogenase (IMPDH) inhibitors was used to validate a virtual screening protocol. By application of a molecular weight filter (80 < MW < 400), 3425 compounds were extracted from an in-house reagent inventory system. Docking of these compounds into a substrate-IMPDH complex 3D structure was performed with the program FlexX three... 

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... 

Mycophenolate sodium (62 Myfortic ) Mycophenolic acid (61) Fatty acid antibiotic NP Microbial Immuno- suppression Inhibits inosine monophosphate dehydrogenase (IMPDH) activity 215-217, 532-560... 

Mycophenolate sodium (62 Myfortic Norvatis, 2003) is an immunosuppressant drug used to prevent rejection in organ transplantation. It is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally... 

Inosinic acid dehydrogenase converts inosinic acid to xanthylic acid which in... 

Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate dehydrogenase, which catalyzes purine synthesis in lymphocytes. It is used in acute tissue rejection responses. 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

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. 

Unlike these nonspecific agents, mycophenolate mofetil (6.4) tends to be a lymphocyte-specific cytotoxic agent. Mycophenolate mofetil is a semisynthetic derivative of mycophe-nolic acid, isolated from the mold Penicillium glaucum. It inhibits both T and B lymphocyte action. Since it inhibits the enzyme inosine monophosphate dehydrogenase, which catalyses purine synthesis in lymphocytes, this agent has a more specific effect on lymphocytes than on other cell types. Mizoribine (6.5) is a closely related drug which inhibits nucleotide synthesis, preferentially in lymphocytes. 

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