Disease relevance of Impdh1

• Mouse IMPD is almost identical to Chinese hamster and human IMPDs and is highly conserved between Escherichia coli and mouse, with a direct amino acid (aa) identity of 39%, which increases to 60% if conserved aa are considered [1].
• Inhibition by tiazofurin of inosine 5'-phosphate dehydrogenase (IMP DH) activity in extracts of ovarian carcinomas [2].
• Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin [3].

High impact information on Impdh1

• Xanthine monophosphate formation was linear for at least 40 min and was inhibited by greater than 95% in the presence of mycophenolic acid, a specific IMPD inhibitor [4].
• It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108 [5].
• MMF inhibits lymphocyte proliferation via a blockade of the enzyme inosine 5'-monophosphate dehydrogenase, an enzyme on which lymphocytes solely depend to generate the purines necessary for DNA/RNA synthesis [6].
• Because of the role of IMPD in the production and balance of GTP and ATP, essential nucleotides for signal transduction, these results suggest that p53 controls cell division signals by regulating purine ribonucleotide metabolism [7].
• 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 [8].

Biological context of Impdh1

• This distinction in regulation pattern suggests that under normal growth conditions, unlike IMPD downregulation, bax and waf1 induction is not a rate-determining event for p53-dependent growth suppression [9].
• We have documented the presence of multiple, processed pseudogenes of type I IMPDH in human and Rhesus monkey genomic DNA, as well as a single functional gene encoding low levels of type I mRNA in human brain, heart, kidney and placenta [10].
• Thus, regulation of IMPDH gene expression is mediated at least in part by the bcr-abl gene product and may therefore be indicative of a specific mechanism of intrinsic resistance to tiazofurin [11].
• The suppressive effects of newly synthesized NAD-analogs, indazole adenine dinucleotides (IAD), on the cellular proliferation of normal and L5178Y cells were investigated in connection with their inhibitory activity on inosine 5'-monophosphate dehydrogenase (IMPD) [12].
• Thus the inhibition of cell growth is probably due to bredinin 5'-phosphate, which inhibits the consecutive enzyme reactions IMP dehydrogenase and GMP synthetase [13].

Anatomical context of Impdh1

• Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses immunoglobulin and cytokine production of B cells [14].
• Mycophenolic acid, an inhibitor of IMP dehydrogenase that is also an immunosuppressive agent, suppresses the cytokine-induced nitric oxide production in mouse and rat vascular endothelial cells [15].
• Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages [16].

Associations of Impdh1 with chemical compounds

• The functional guanine-nucleotide-precursor pools for DNA are rather small; further, the depletion of the small GMP pool, but not that of GDP, GTP and dGTP, correlated well with the inhibition of DNA synthesis by mycophenolic acid, an IMP dehydrogenase inhibitor [17].
• 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) [18].
• MPA reversibly inhibits inosine 5'-monophosphate dehydrogenase, an enzyme involved in the de novo guanosine synthesis [19].
• Human inosine monophosphate dehydrogenase activity is the result of the expression of two independent but closely related genes, termed IMPDH type I and type II [10].
• Other NAD utilizing enzymes, including representative dehydrogenases and poly ADP ribose polymerase, were, by comparison to mammalian IMPD, resistant to inhibition by TAD [20].

Analytical, diagnostic and therapeutic context of Impdh1

• Northern blot analysis of chicken RNA revealed a single mRNA species that hybridized to human IMPDH type I and II probes [10].
• This increase in enzyme activity was a result of 2-fold increased IMPDH protein as determined by immunoblotting [11].

References