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Nature Cell Biology Aug 2019In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking...
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
Topics: Carcinogenesis; Cell Line, Tumor; Cell Nucleolus; Cell Proliferation; Cell Transformation, Neoplastic; Glioblastoma; Humans; IMP Dehydrogenase; RNA, Ribosomal
PubMed: 31371825
DOI: 10.1038/s41556-019-0363-9 -
Chemical Reviews Jul 2009
Review
Topics: Catalytic Domain; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Kinetics; Neoplasms; Protein Structure, Tertiary; Substrate Specificity
PubMed: 19480389
DOI: 10.1021/cr900021w -
Nucleosides, Nucleotides & Nucleic Acids Jun 2008Many retinal diseases are caused by mutations in photoreceptor-specific proteins. However, retinal disease can also result from mutations in widely expressed proteins.... (Review)
Review
Many retinal diseases are caused by mutations in photoreceptor-specific proteins. However, retinal disease can also result from mutations in widely expressed proteins. One such protein is inosine monophosphate dehydrogenase type 1 (IMPDH1), which catalyzes a key step in guanine nucleotide biosynthesis and also binds single-stranded nucleic acids. The pathogenic IMPDH1 mutations are in or near the CBS domains and do not affect enzymatic activity. However, these mutations do decrease the affinity and specificity of single-stranded nucleic acid binding. These observations suggest that IMPDH1 has a previously unappreciated role in RNA metabolism that is crucial for photoreceptor function.
Topics: Amino Acid Sequence; Animals; DNA, Single-Stranded; Humans; IMP Dehydrogenase; Molecular Sequence Data; Mutation; RNA, Messenger; Retinitis Pigmentosa
PubMed: 18600550
DOI: 10.1080/15257770802146486 -
Pigment Cell & Melanoma Research May 2020Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to...
Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH-based RR structures. Forty-five ALM paraffin-embedded tissue samples and 59 melanocytic nevi were probed with anti-IMPDH2 antibody. Both the rod- and ring-shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR-positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR-positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR-positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR-positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR-low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.
Topics: Genetic Heterogeneity; Humans; IMP Dehydrogenase; Melanoma; Nevus, Pigmented
PubMed: 31883196
DOI: 10.1111/pcmr.12854 -
Microbiology Spectrum Aug 2023Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the...
Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.026 to 0.89 μM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the postentry step to reduce the intracellular production of virions. Knockdown of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. This evidence shows that IMPDH is a potential target for the development of anti-MPXV agents. Mpox is a zoonotic disease caused by infection with the mpox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against mpox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against mpox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-mpox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited mpox virus propagation and exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested IMP dehydrogenase as a potential target for the development of anti-mpox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-mpox virus activity than mycophenolic acid.
Topics: Guanosine; IMP Dehydrogenase; Mycophenolic Acid; Trifluridine; Monkeypox virus
PubMed: 37409948
DOI: 10.1128/spectrum.00566-23 -
Current Opinion in Chemical Biology Oct 2006Textbooks describe enzymes as relatively rigid templates for the transition state of a chemical reaction, and indeed an enzyme such as chymotrypsin, which catalyzes a... (Review)
Review
Textbooks describe enzymes as relatively rigid templates for the transition state of a chemical reaction, and indeed an enzyme such as chymotrypsin, which catalyzes a relatively simple hydrolysis reaction, is reasonably well described by this model. Inosine monophosphate dehydrogenase (IMPDH) undergoes a remarkable array of conformational transitions in the course of a complicated catalytic cycle, offering a dramatic counterexample to this view. IMPDH displays several other unusual mechanistic features, including an Arg residue that may act as a general base catalyst and a dynamic monovalent cation site. Further, IMPDH appears to be involved in 'moon-lighting' functions that may require additional conformational states. How the balance between conformational states is maintained and how the various conformational states interconvert is only beginning to be understood.
Topics: Animals; Binding Sites; Catalysis; Enzyme Activation; Enzyme Inhibitors; Hydrogen-Ion Concentration; IMP Dehydrogenase; Models, Molecular; Molecular Structure; Nucleic Acids; Protein Conformation
PubMed: 16919497
DOI: 10.1016/j.cbpa.2006.08.005 -
Current Medicinal Chemistry 2011Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of guanosine 5'-monophosphate (GMP) biosynthesis, and thus regulates the guanine... (Review)
Review
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of guanosine 5'-monophosphate (GMP) biosynthesis, and thus regulates the guanine nucleotide pool, which in turn governs proliferation. Human IMPDHs are validated targets for immunosuppressive, antiviral and anticancer drugs, but as yet microbial IMPDHs have not been exploited in antimicrobial chemotherapy. Selective inhibitors of IMPDH from Cryptosporidium parvum have recently been discovered that display anti-parasitic activity in cell culture models of infection. X-ray crystal structure and mutagenesis experiments identified the structural features that determine inhibitor susceptibility. These features are found in IMPDHs from a wide variety of pathogenic bacteria, including select agents and multiply drug resistant strains. A second generation inhibitor displays antibacterial activity against Helicobacter pylori, demonstrating the antibiotic potential of IMPDH inhibitors.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Species Specificity
PubMed: 21517780
DOI: 10.2174/092986711795590129 -
Nihon Rinsho. Japanese Journal of... Jan 2003
Review
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Feedback, Physiological; Genes, Dominant; Guanosine Monophosphate; Humans; IMP Dehydrogenase; Immunosuppressive Agents; Mycophenolic Acid; Pigment Epithelium of Eye; Protein Conformation; Protein Structure, Tertiary; Purine Nucleotides; Retinal Degeneration; Ribavirin; Ribonucleosides
PubMed: 12629691
DOI: No ID Found -
Proceedings of the National Academy of... Jul 2017Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good...
Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.
Topics: Allosteric Regulation; Amino Acid Substitution; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Catalytic Domain; Cell Line; Cysteine; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Inflammation; Isoflavones; Mice, Inbred BALB C; Microglia; Molecular Targeted Therapy; Structure-Activity Relationship
PubMed: 28674004
DOI: 10.1073/pnas.1706778114 -
Current Medicinal Chemistry Jul 1999Inosine monophosphate dehydrogenase (IMPDH, E.C. 1.1.1.205) is recognized as an important target for both antileukemic and immunosuppressive therapy. IMPDH catalyzes the... (Review)
Review
Inosine monophosphate dehydrogenase (IMPDH, E.C. 1.1.1.205) is recognized as an important target for both antileukemic and immunosuppressive therapy. IMPDH catalyzes the NAD-dependent oxidation of inosine 5 monophosphate (IMP) to xanthosine 5 monophosphate. Several classes of IMPDH inhibitors are now in use or under development. These include agents that bind at either the substrate site (e.g. ribavirin and mizoribine) or at the NAD site (mycophenolic acid and thiazole-4-carboxamide adenine dinucleotide). All suffer from some degree of toxicity and/or susceptibility to metabolic inactivation. The finding that IMPDH exists as two isoforms, one of which (type II) is induced in tumor cells, has led to the search for potentially more effective isoform-specific agents. Recently, a number of crystal structures of IMPDH have become available. These include structures of the human type II, hamster, Tritrichomonas foetus, Streptococcus pyogenes and Borrelia burgdorferi enzymes. Each structure crystallizes as a tetramer of a/b barrels, with the active site located partly at the monomer-monomer interface. The substrate and cofactor bind in a continuous cleft on the C-terminal face of each barrel. The IMP base is well positioned to stack against the NAD nicotinamide ring to facilitate hydride transfer. The active site cleft is further bounded by a highly flexible flap and loop. These structures reveal enzyme-ligand interactions which suggest strategies for the design of improved inhibitors.
Topics: Amino Acids; Animals; Binding Sites; Borrelia burgdorferi Group; Cricetinae; Crystallography, X-Ray; Drug Design; Humans; IMP Dehydrogenase; Models, Biological; Models, Molecular; Protein Binding; Protein Conformation; Streptococcus pyogenes; Tritrichomonas foetus
PubMed: 10390598
DOI: No ID Found