Disease relevance of IMPDH1

• Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration [1].
• PURPOSE: To determine the presence and frequency of mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa (ADRP), and to characterize the clinical characteristics of patients with the Lys238Arg mutation in the IMPDH1 gene [2].
• CONCLUSION: In this family with a mutation in IMPDH1, we found a specific phenotype with rod function affected more than cone function, foveal edema, and central retinal function preserved for a long period of time [3].
• PURPOSE: The purpose of this study was to investigate retinal inosine monophosphate dehydrogenase 1 (IMPDH1) transcripts and proteins to gain an understanding of how mutations in IMPDH1 lead to retinal disease [4].
• Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts [5].

High impact information on IMPDH1

• The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction [6].
• IMPDH plays a central role in B and T lymphocyte replication [6].
• IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain [6].
• The complex, in combination with mutagenesis and kinetic data, provides a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule [6].
• A new study establishes that Bateman domains bind adenosyl compounds and regulate IMP dehydrogenase, CBS, chloride channels, and AMP-activated protein kinase [7].

Chemical compound and disease context of IMPDH1

• Sensitization of human erythroleukemia K562 cells resistant to methotrexate by inhibiting IMPDH [8].
• In patients coinfected and treated for both HIV-1 and hepatitis C virus (HCV), administration of ribavirin (RBV) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase [9].
• Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC) [10].
• Recently, we have reported that inosine 5'-monophosphate dehydrogenase inhibitors, such as mycophenolic acid (MPA), induce the differentiation of PC-3 cells, which are derived from a human androgen-independent prostate cancer, into cells with a phenotype resembling maturing prostate secretory cells [11].
• Modulation of the guanylate pathway in glioblastoma by inhibition of IMP dehydrogenase with tumor specific agents such as tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) appears to be a rational therapeutic approach [12].

Biological context of IMPDH1

• Expression of mutant IMPDH1 proteins in bacterial and mammalian cells, together with computational simulations, indicate that protein misfolding and aggregation, rather than reduced IMPDH1 enzyme activity, is the likely cause of the severe phenotype experienced by human subjects [13].
• Assignment of the human type I IMP dehydrogenase gene (IMPDH1) to chromosome 7q31.3-q32) [14].
• METHODS: All 14 coding exons of the IMPDH1 gene were directly sequenced in 96 unrelated patients with ADRP [2].
• The IMPDH-like sequence 323F4 was regionally localized by PCR analysis of a panel of somatic cell hybrids containing different portions of human chromosome 16 to 16p13.3-13.12, between the breakpoints found in hybrids CY196/CY197 and CY198 [15].
• We determined the chromosomal localization and structure of the gene encoding human type II inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205), an enzyme associated with cellular proliferation, malignant transformation, and differentiation [16].

Anatomical context of IMPDH1

• A screen of retinal transcripts comparing retinas from normal mice to retinas from crx-/crx- knockout mice (with poorly differentiated photoreceptors) demonstrated a 6-fold reduction in one candidate, inosine monophosphate dehydrogenase 1 (IMPDH1; EC 1.1.1.205) [17].
• Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes [5].
• To assess this role we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts [5].
• These findings suggest that several of these nuclear factors may play a critical role in the regulation of IMPDH type II gene expression during T lymphocyte activation [18].
• Two selective IMPDH inhibitors (mycophenolic acid and mizoribine) reduced IMPDH activity in all cell lines, and, with virtually identical concentration-response curves, inhibited DNA synthesis (assessed as bromodeoxyuridine incorporation) in response to glucose, serum, or ketoisocaproate [19].

Associations of IMPDH1 with chemical compounds

• IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides [17].
• Production of fluorescent reduced nicotinamide adenine dinucleotide (NADH) was used to measure enzymatic activity of mutant IMPDH1 proteins [1].
• The aspartic acid at codon 226 is conserved in all IMPDH genes, in all species examined, including bacteria, suggesting that this mutation is highly deleterious [17].
• DNA sequencing of affected individuals from the two American RP10 families revealed a GAC-->AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families [17].
• As lymphocytes depend more than other cell types on de novo synthesis of purines, IMPDH inhibitors such as mycophenolic acid (MPA) can selectively expand lymphocytes overexpressing the enzymes [20].

Physical interactions of IMPDH1

• A yeast-based two-hybrid system was employed which identified inosine-5' monophosphate dehydrogenase (IMPDH) type II as specifically interacting with PKB/Akts PH domain [21].

Regulatory relationships of IMPDH1

• Changes in IMPDH2 mRNA levels were confirmed and functional analyses were performed by inhibiting IMPDH with either benzamide riboside, mycophenolic acid, or tiazofurin [8].
• Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells [22].
• In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity [23].

Other interactions of IMPDH1

• Identification and regional localization of a human IMP dehydrogenase-like locus (IMPDHL1) at 16p13.13 [15].
• On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa [13].
• Chromosomal localization and structure of the human type II IMP dehydrogenase gene (IMPDH2) [16].
• For a given amount of remaining visual field, there was a larger ERG amplitude in IMPDH1-carrying patients (average 0.5-Hz ERG/visual field ratio = 9.5 nV/deg(2)) compared with groups of patients with the RP1 mutation Arg677End (2.8 nV/deg(2)), the rhodopsin (RHO) mutation Pro23His (5.1 nV/deg(2)), or the RHO mutation Pro347Leu (1.7 nV/deg(2)) [24].
• Cultivation of HUVECs in the absence of guanine enhanced further ICAM-1 expression during IMPDH inhibition [25].
• We find that IMPDH1 is associated with polyribosomes containing rhodopsin mRNA [26].

Analytical, diagnostic and therapeutic context of IMPDH1

• METHODS: A variety of methods were used to address the unique features of IMPDH1 in the retina, including Northern blot analysis, serial analysis of gene expression (SAGE), immunohistochemistry, transcript sequencing, and Western blot analysis [4].
• We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8 [17].
• IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, is a promising target in antileukemic chemotherapy [27].
• Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs [28].
• Both of the two isoforms of IMPDH (constitutive type 1 and inducible type 2) were identified using RT-PCR in transformed beta cells or in intact islets [19].

References