Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs.

Collart, F.; Huberman, Eliezer

doi:10.1016/s0021-9258(19)37654-9

Cited by 143 publications

(19 citation statements)

References 18 publications

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“…Cancer cells often display altered expression of enzymes for the de novo biosynthesis of nucleotides, especially purines, highlighting their dependency on these pathways and substrates [10][11][12][13][14][15][16] . In particular, the de novo biosynthesis of guanosine monophosphate (GMP) is driven by the consecutive enzymatic action of inosine monophosphate dehydrogenase 1 and 2 (IMPDH1, 2) and guanosine monophosphate synthase (GMPS), which convert inosine monophosphate (IMP) into xanthosine monophosphate (XMP) 17 and XMP into GMP 18 , respectively. GMP reductase (GMPR) is a functional antagonist of IMPDH1/2 and GMPS that reduces GMP to IMP (Supplementary Fig.…”

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confidence: 99%

Regulation of local GTP availability controls RAC1 activity and cell invasion

et al. 2021

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Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells.

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Regulation of local GTP availability controls RAC1 activity and cell invasion

et al. 2021

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“…This is the committed, and probably rate-limiting, step in the de noVo pathway for guanine nucleotide biosynthesis (Crabtree & Henderson, 1971;Snyder et al, 1972;Jackson et al, 1975;Weber, 1983). IMPDH homologues identified in bacteria, protozoa, and mammals share 30%-40% sequence identity (Collart & Huberman, 1988;Natsumeda et al, 1990;Beck et al, 1994). In some mammalian species two isoforms have been identified.…”

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confidence: 99%

Inhibition of IMPDH by Mycophenolic Acid: Dissection of Forward and Reverse Pathways Using Capillary Electrophoresis

et al. 1996

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The objective of this work was to contribute to the understanding of mechanisms for IMPDH inhibition. We over-expressed hamster type II IMPDH in Escherichia coli, purified the protein to apparent homogeneity, and used capillary electrophoresis to quantify enzyme turnover events accompanying inhibition by mycophenolic acid (MPA). We dissected two convergent pathways leading to MPA-inhibition; a rapid "forward" pathway beginning with substrates and linked to enzyme catalysis, and a slower "reverse" pathway apparently not involving catalysis. MPA-inhibition occurred rapidly in the forward direction by interrupting the enzyme turnover cycle, after IMP and NAD+ binding, after hydride transfer, and after NADH release. Slow inhibition, without substrate turnover, was achieved by incubating free enzyme with excess XMP and MPA. We propose that mycophenolic acid inhibits IMPDH by trapping a transient covalent product of the hydride transfer reaction (IMPDH approximately XMP*) before a final hydrolysis step that precedes XMP and enzyme release in the forward reaction pathway. Understanding the ligand occupancy of the protein has also proven important for producing homogeneous, chemically defined complexes for structural studies. IMPDH samples inhibited by MPA in the forward and reverse pathways yielded similar, high-quality crystals that are currently undergoing X-ray diffraction analyses.

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“…There are two isoforms of IMPDH in mammals, IMPDH1 and IMPDH2. These two members share 84% aminio acid sequence identity and have virtually indistinguishable catalytic activity, but their tissue expression patterns and physiological importance differ largely (Collart and Huberman, 1988;Carr et al, 1993;Senda and Natsumeda, 1994;Hager et al, 1995). IMPDH2 is the dominant isoform expressed in most tissues of human, while IMPDH1 is found to be constitutively expressed at low levels in most tissues other than retina, spleen, and resting peripheral blood mononuclear cells (Senda and Natsumeda, 1994;Jain et al, 2004;Bowne et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Coordinated Formation of IMPDH2 Cytoophidium in Mouse Oocytes and Granulosa Cells

Zhang

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme catalyzing de novo biosynthesis of guanine nucleotides, aggregates under certain circumstances into a type of non-membranous filamentous macrostructure termed “cytoophidium” or “rod and ring” in several types of cells. However, the biological significance and underlying mechanism of IMPDH assembling into cytoophidium remain elusive. In mouse ovaries, IMPDH is reported to be crucial for the maintenance of oocyte–follicle developmental synchrony by providing GTP substrate for granulosa cell natriuretic peptide C/natriuretic peptide receptor 2 (NPPC/NPR2) system to produce cGMP for sustaining oocyte meiotic arrest. Oocytes and the associated somatic cells in the ovary hence render an exciting model system for exploring the functional significance of formation of IMPDH cytoophidium within the cell. We report here that IMPDH2 cytoophidium forms in vivo in the growing oocytes naturally and in vitro in the cumulus-enclosed oocytes treated with IMPDH inhibitor mycophenolic acid (MPA). Inhibition of IMPDH activity in oocytes and preimplantation embryos compromises oocyte meiotic and developmental competences and the development of embryos beyond the 4-cell stage, respectively. IMPDH cytoopidium also forms in vivo in the granulosa cells of the preovulatory follicles after the surge of luteinizing hormone (LH), which coincides with the resumption of oocyte meiosis and the reduction of IMPDH2 protein expression. In cultured COCs, MPA-treatment causes the simultaneous formation of IMPDH cytoopidium in cumulus cells and the resumption of meiosis in oocytes, which is mediated by the MTOR pathway and is prevented by guanosine supplementation. Therefore, our results indicate that cytoophidia do form in the oocytes and granulosa cells at particular stages of development, which may contribute to the oocyte acquisition of meiotic and developmental competences and the induction of meiosis re-initiation by the LH surge, respectively.

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Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs.

Cited by 143 publications

References 18 publications

Regulation of local GTP availability controls RAC1 activity and cell invasion

Regulation of local GTP availability controls RAC1 activity and cell invasion

Inhibition of IMPDH by Mycophenolic Acid: Dissection of Forward and Reverse Pathways Using Capillary Electrophoresis

Coordinated Formation of IMPDH2 Cytoophidium in Mouse Oocytes and Granulosa Cells

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