Disease relevance of Impdh2

• Increased activity, amount, and altered kinetic properties of IMP dehydrogenase from mycophenolic acid-resistant neuroblastoma cells [1].
• These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies [2].
• Following the parenteral administration of tiazofurin, 2-beta D-ribofuranosylthiazole-4-carboxamide (thiazole nucleoside, TR), a potent but reversible inhibitor of IMP dehydrogenase is generated in subcutaneous nodules of the P388 leukemia [3].
• The predominant IMPDH isoform (Type II) detected in a number of human cancers, such as leukemias, ovarian and breast, was inhibited by the compounds yielding IC50 values in the microM range [4].
• These results suggest that a genetic defect in IMP dehydrogenase activity in humans might lead to excessive purine overproduction with subsequent hyperuricemia and gout [5].

High impact information on Impdh2

• Inosine 5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides, which are also synthesized from guanine by a salvage reaction catalyzed by the X chromosome-linked enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) [6].
• Lymphocytes from IMPDH II(+/-) heterozygous mice are normal with respect to subpopulation distribution and respond normally to a variety of mitogenic stimuli [6].
• Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene [6].
• However, mice with an IMPDH II(+/-), HPRT(-/o) genotype demonstrate significantly decreased lymphocyte responsiveness to stimulation with anti-CD3 and anti-CD28 antibodies and show a 30% mean reduction in GTP levels in lymphocytes activated by these antibodies [6].
• We have demonstrated that mycophenolic acid (MPA), a specific inosine monophosphate dehydrogenase (IMPDH) inhibitor that results in depletion of intracellular guanine nucleotides, is synergistic with imatinib in inducing apoptosis in Bcr-Abl-expressing cell lines [7].

Chemical compound and disease context of Impdh2

• Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM) [8].
• Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin [9].
• Inhibition of IMP dehydrogenase in AS-30D hepatoma cells in suspension culture resulted in a pronounced and selective reduction of guanine nucleotide pools [10].
• Selective guanosine phosphate deficiency in hepatoma cells induced by inhibitors of IMP dehydrogenase [10].

Biological context of Impdh2

• A 4-h treatment of the cell lines at IC50 doses showed 48% and 23% reductions in IMP dehydrogenase in L1210/0 and L1210/3-DG, respectively [11].
• Evidence was also obtained for IMP dehydrogenase having undergone gene amplification [12].
• The nucleotide sequence of IMP dehydrogenase cDNA from NB-Myco cells revealed four nucleotide changes [12].
• Gene amplification and dual point mutations of mouse IMP dehydrogenase associated with cellular resistance to mycophenolic acid [12].
• DNA dot blot analysis showed a 25-fold increase in IMP dehydrogenase gene copy number and restriction enzyme analysis revealed similar gene structure for NB and NB-myco cells [12].

Anatomical context of Impdh2

• VX-148 does not inhibit proliferation of nonlymphoid cell types such as fibroblasts, indicating selectivity for inhibition of IMPDH activity [13].
• Chemical modification of the lead compound resulted in pyridazine derivatives with enhanced potency against IMPDH and guanine nucleotide synthesis in cultured cells in vitro and also against guanine nucleotide synthesis in the mouse spleen in vivo [14].
• The IMP dehydrogenase inhibitors, bredinin and mycophenolic acid (MA), induced, in a dose-dependent manner, the resumption of maturation in cumulus cell-enclosed oocytes maintained in meiotic arrest by hypoxanthine but had no effect on denuded oocytes [15].
• BACKGROUND: Mycophenolate mofetil (MMF) is a highly potent immunosuppressant that suppresses the proliferation of T and B cells by the uncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH) [16].
• Incubation of K562 cells with selenophenfurin resulted in inhibition of IMP dehydrogenase (IMPDH) (76%) and an increase in IMP pools (14.5-fold) with a concurrent decrease in GTP levels (58%) [17].

Associations of Impdh2 with chemical compounds

• Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides [2].
• On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine [18].
• In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M [18].
• Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase [18].
• In order to exert its antitumor effects, the C-nucleoside tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted to the dinucleotide TAD (thiazole-4-carboxamide adenine dinucleotide), an inhibitor of IMP dehydrogenase (IMPD) [19].

Other interactions of Impdh2

• The synthetic material was indistinguishable from biosynthesized TAD as judged by its HPLC behavior, NMR, UV and mass spectra, enzymatic resistance to alkaline phosphatase and susceptibility to venom phosphodiesterase, IMP dehydrogenase inhibitory activity, and cytotoxicity [20].

Analytical, diagnostic and therapeutic context of Impdh2

• Since inhibitors of IMPDH are in clinical use as immunosuppressive agents, we have examined the consequences of knocking out the IMPDH type II enzyme by gene targeting in a mouse model [6].
• Purification and sequence analysis confirmed that the abundant protein was IMP dehydrogenase [1].
• These selections were further refined to discern those likely to have a role in catalysis using information derived from the bacterial and mammalian IMPDH crystal structures and site-specific mutagenesis [21].
• We used sequence alignments of IMPDH proteins to identify sequence signatures associated with bacterial or eukaryotic IMPDH enzymes [21].
• Mizoribine (MZ) also inhibits IMPDH in a competitive manner and is used clinically for organ transplantation in Japan as an immunosuppressant with fewer adverse gastrointestinal effects [16].

References