Inosine monophosphate dehydrogenase IMPDH

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. 

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... 

Selenazofurin (158), selenophenfurin (159), and dinucleosides such as 160 (Fig. 10), are potent inosine monophosphate dehydrogenase (IMPDH) inhibitors and have pronounced antitumor activity in animals and broad spectrum antiviral as well as maturation-inducing activities [262-264], The inhibitory effects of heterocyclic organoselenium compounds such as ebselen and some of its derivatives have been demonstrated on 15-LOXs [21, 265],... 

Inosine Monophosphate Dehydrogenase. Proliferative cells such as lymphocytes have high demands for the rapid supply of nucleotides to support DNA and RNA synthesis, as do viruses during their proliferative phase. The first dedicated step in the de novo biosynthesis of guanine nucleotides is conversion of inosinate to XMP, catalyzed by inosine monophosphate dehydrogenase (IMPDH). 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Inosine monophosphate dehydrogenase (IMPDH) is an enzyme in the de novo synthetic pathway of guanosine nucleotides. Pitts et al. have identified several series of novel triazine inhibitors of the enzyme IMPDH II. These compounds demonstrate that the urea or diamide isosteres can be replaced effectively by heterocycles <2002BML2137>. 

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 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... 

Figure 4 Pathway of thiopurine metabolism. Abbreviations TPMT, thiopurine methyltransferase XO, xanthineoxidase HPRT, hypoxanthine guanine phosphori-bosyltransferase IMPDH, inosine monophosphate dehydrogenase.

FIGURE 13.7 Thiopurine metabolic pathways. TPMT, ThiopLirine methyl transferase XO, xantlaine oxidase HPRX, hypoxanthine guanine phosphoribosyltransferase IMPDH, inosine monophosphate dehydrogenase. 

Figure 3. Compartmentalization of the purine salvage pathway of Leishmania. Abbreviations are as follows AAH, adenine aminohydrolase XPRT, xanthine phosphoribosyltransferase HGPRT, hypoxanthine-guaninephosphoribosyltransferase ADSS, adenylosuccinate synthetase ASL, adenylosuccinate lyase IMPDH, inosine monophosphate dehydrogenase GMPS, gua-nosine monophosphate synthase GDA, guanine deaminase AMPDA, adenosine monophosphate deaminase GMPR, guanosine monophosphate reductase APRT, adenine phosphoribosyltransferase AK, adenosine kinase. Enzymes that have been localized are shown in black and those that are predicted to be in the denoted locations are depicted in gray.

Figure 1 The metabolism of azathioprine and mercaptopurine Key AO, aldehyde ojddase GMPS, guanine monophosphate synthetase HPRT, hypoxanthine phosphoribosyl transferase IMPDH, inosine monophosphate dehydrogenase ITPA, inosine triphosphate pyrophosphohydrolase TPMT, thiopurine methyltransfer-ase XO/XDH, xanthine oxidase/dehydrogenase.

Fig. 29.2 Caffeine is produced from xanthosine derived from four routes (1) inosine-5 -monophosphate (IMP) originating from de novo purine synthesis (de novo route), (2) adenosine released from the 5-adenosyhnethionine (SAM) cycle, (3) the cellular adenosine nucleotide pool (AMP route), and (4) the guanine nucleotide pool (GMP route). Enzymes AMPDA AMP deaminase, APRT adenine phosphorihosyltransferase, AK adenosine kinase, ARN adenosine nucleosidase, GRD guanine deaminase, IMPDH IMP dehydrogenase, 5 NT 5 -nucleotidase...

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