Affinage

IMPDH2

Inosine-5'-monophosphate dehydrogenase 2 · UniProt P12268

Length
514 aa
Mass
55.8 kDa
Annotated
2026-06-10
72 papers in source corpus 29 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IMPDH2 catalyzes the rate-limiting, first committed step of de novo guanine nucleotide biosynthesis, oxidizing IMP toward XMP/GTP, and couples this metabolic output to cell proliferation and tissue development (PMID:26546974, PMID:32702086, PMID:38692012). Its activity is gated by an allosteric mechanism in which GTP binding to regulatory Bateman/CBS domains favors a less active conformation, and reversible polymerization into filaments stabilizes active conformations that resist GTP feedback inhibition, allowing the enzyme to sustain output when guanine nucleotide pools must expand (PMID:31999252). IMPDH2 is the structural building block of cytoplasmic rod/ring (RR) bodies and co-assembles with CTPS in a manner dictated by which biosynthetic pathway is pharmacologically inhibited (PMID:25601894, PMID:26165495). Layered post-translational control tunes this output: CDK1 phosphorylates S122 to attenuate catalysis, an inhibition reversed by FGFR-driven PP2A (PPP2CA–PPP2R1A) dephosphorylation that activates the enzyme and promotes S-phase completion (PMID:39739531), while HSPA6-recruited ROCK2 phosphorylates S416 to activate IMPDH2 and limit DNA damage (PMID:42234559). Enzyme abundance is set by ubiquitin-dependent turnover, with K48-chain removal by USP5 stabilizing the protein, JOSD2 cleaving K63 chains at K134 to restrain IMPDH2-driven NF-κB signaling, and ANKRD9 governing a vesicle-to-filament transition that stabilizes IMPDH2 under nutrient limitation (PMID:40164869, PMID:40177575, PMID:31337707). Beyond cytoplasmic metabolism, chromatin-associated IMPDH2 binds PARP1 and controls nuclear NAD+ availability to fine-tune the DNA damage response (PMID:39532854). Gain-of-function point mutations and the S160del variant cause dystonia and neurodevelopmental disorders by shifting the conformational equilibrium toward the active state and disrupting GTP allostery and filament assembly, whereas loss of Impdh2 in neural crest impairs enteric nervous system and craniofacial development (PMID:37414152, PMID:41343675, PMID:26546974).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2009 Medium

    Established that IMPDH2 expression level is set transcriptionally and that a regulatory promoter element controls output, framing the gene as dosage-sensitive before its catalytic regulation was understood.

    Evidence Luciferase promoter-reporter assays of wild-type vs. CRE-disrupting c.-95T>G constructs in HEK293 and Jurkat cells

    PMID:19810816

    Open questions at the time
    • Does not identify the trans-acting CRE-binding factor
    • No link to physiological signaling that engages this promoter element
  2. 2010 Medium

    Showed that a coding allozyme reduces enzyme activity chiefly by accelerating protein degradation, introducing protein stability as a determinant of IMPDH2 functional output.

    Evidence Resequencing, allozyme activity and degradation assays, and X-ray crystallography of IMPDH2

    PMID:20718729

    Open questions at the time
    • Degradation machinery not identified
    • Does not connect stability to allosteric regulation
  3. 2015 Medium

    Defined IMPDH2 as the essential structural component of cytoplasmic rod/ring bodies and showed assembly composition is dictated by which nucleotide pathway is inhibited, establishing polymerization as a regulated cellular phenomenon.

    Evidence Anti-IMPDH2 antibody microinjection and GFP-IMPDH2 imaging in COS-7; immunofluorescence with ribavirin/MPA/DON and CTPS co-assembly across cell lines

    PMID:25601894 PMID:26165495

    Open questions at the time
    • Functional consequence of RR assembly on enzyme activity not yet established
    • Structural basis of filament formation undefined
  4. 2015 High

    Demonstrated in vivo that IMPDH2-mediated GTP synthesis is required for neural crest development, moving the gene from a housekeeping enzyme to a developmentally essential factor.

    Evidence Wnt1-Cre conditional Impdh2 knockout with lineage tracing and developmental histology in mice

    PMID:26546974

    Open questions at the time
    • Does not resolve which downstream GTP-dependent processes are limiting
    • Cell-autonomous vs. non-autonomous requirement not dissected
  5. 2017 High

    Identified IMPDH2 as the isoform-selective intracellular target of the cyclophilin A–sanglifehrin A complex acting through the CBS domain, revealing the regulatory CBS/Bateman region as a ligand-binding hub distinct from the catalytic site.

    Evidence Affinity pulldown, reciprocal Co-IP, CBS-domain mapping, enzymatic assays, and IMPDH1/IMPDH2 isoform selectivity tests

    PMID:28076787

    Open questions at the time
    • Ternary complex does not inhibit catalysis, so mechanism of growth modulation is unresolved
    • Endogenous physiological ligand of the CBS domain not addressed
  6. 2019 High

    Connected IMPDH2 abundance to nutrient sensing by showing ANKRD9 drives a vesicle-to-filament transition that switches IMPDH2 between degradation and stabilization, linking polymerization to protein turnover.

    Evidence Reciprocal Co-IP, fractionation, Cys109/110 mutagenesis, ANKRD9 knockdown/overexpression, and guanosine rescue

    PMID:31337707

    Open questions at the time
    • Whether ANKRD9 is the E3 adaptor or a competing stabilizer is not fully resolved
    • Mechanism coupling filament state to ubiquitin machinery undefined
  7. 2020 High

    Provided the structural mechanism of filament-based allostery, showing polymerization stabilizes conformations resistant to GTP feedback inhibition—the defining regulatory logic of IMPDH2.

    Evidence Cryo-EM of active and inactive IMPDH2 conformations correlated with enzymatic activity

    PMID:31999252

    Open questions at the time
    • In vivo triggers that initiate polymerization not defined structurally
    • Does not address post-translational inputs onto the conformational switch
  8. 2020 Medium

    Linked IMPDH2-driven GTP supply to anabolic transcription, showing it powers RNA polymerase I/III activity and nucleolar enlargement in cancer cells.

    Evidence IMPDH2 knockdown/overexpression with GTP measurement, Pol I/III activity assays, and nucleolar size analysis in glioblastoma

    PMID:32702086

    Open questions at the time
    • Limited methodological detail
    • Direct vs. indirect coupling of GTP pools to polymerase activity not dissected
  9. 2023 High

    Established gain-of-function dysregulation as the disease mechanism, showing dystonia/neurodevelopmental mutations shift the conformational equilibrium toward the active state and disrupt GTP allostery.

    Evidence Cryo-EM of a disease mutant plus GTP-inhibition enzymatic assays and patient variant identification

    PMID:37414152

    Open questions at the time
    • Cellular and neuronal consequences of unrestrained activity not directly tested
    • Genotype–phenotype range across mutations not defined
  10. 2023 Medium

    Expanded the IMPDH2 interactome into oncogenic and survival pathways through partners FANCI and B7-H3 that modulate its stability and stress resistance.

    Evidence Co-IP with FANCI/IMPDH2 and B7-H3/IMPDH2, knockdown/rescue, and oxidative stress and proliferation assays in lung cancer cells

    PMID:32021289 PMID:37444640

    Open questions at the time
    • B7-H3 interaction rests on a single Co-IP without reciprocal validation
    • Whether these partners act on catalysis or stability is not fully separated
  11. 2024 High

    Defined a kinase-phosphatase switch on S122, showing CDK1 phosphorylation suppresses activity while FGFR-driven PP2A dephosphorylation activates the enzyme to license S-phase, integrating IMPDH2 into proliferative signaling.

    Evidence In vitro CDK1 kinase assay, phosphoproteomics, S122 mutagenesis, Co-IP of the PPP2CA–PPP2R1A–IMPDH2 complex, and FGFR manipulation

    PMID:39739531

    Open questions at the time
    • Interplay between S122 status and filament assembly not resolved
    • Whether dephosphorylation acts directly on allostery or catalysis distinct
  12. 2024 High

    Revealed a nuclear, chromatin-associated role for IMPDH2 in tuning the DNA damage response via PARP1 through control of nuclear NAD+ availability.

    Evidence Chromatin fractionation, IMPDH2–PARP1 Co-IP, nuclear NAD+ quantification, and nuclear-restriction/knockdown DNA-damage assays in TNBC

    PMID:39532854

    Open questions at the time
    • Mechanism by which IMPDH2 reaches chromatin not defined
    • Whether catalytic activity or scaffolding controls nuclear NAD+ unclear
  13. 2024 Medium

    Established that IMPDH2 turnover is set by deubiquitinases, with USP5 removing K48 chains to stabilize the protein and JOSD2 cleaving K63 chains at K134 to restrain its pro-inflammatory NF-κB output.

    Evidence Co-IP, domain mapping, ubiquitin chain-type/site-specific deubiquitination assays, and myeloid JOSD2 knockout colitis model

    PMID:40164869 PMID:40177575

    Open questions at the time
    • E3 ligases generating these chains not identified
    • How K63-ubiquitination at K134 enhances NF-κB activity mechanistically unclear
  14. 2024 Medium

    Demonstrated tissue-specific developmental and metabolic requirements for IMPDH2 in osteoclast differentiation and adipocyte precursor expansion, the latter mechanistically traced to nucleotide (XMP) provision.

    Evidence LysM-Cre and APC-specific conditional Impdh2 knockouts with transcriptomics, bone-loss and high-fat-diet models, and XMP rescue

    PMID:38692012 PMID:38959733

    Open questions at the time
    • Whether the osteoclast mitochondrial defect is direct or secondary to nucleotide depletion is unresolved
    • Cell-type specificity of these requirements not generalized
  15. 2024 Medium

    Showed that IMPDH2 filament assembly is physiologically protective and context-dependent, buffering GTP deprivation in neurons and regulating oocyte meiotic competence via MTOR.

    Evidence AMPD2-deficient mouse model with regional filament quantification and dominant-negative IMPDH2 in human neural progenitors; ovarian/cumulus-oocyte imaging with MPA, guanosine rescue, and MTOR inhibition

    PMID:34124077 PMID:39075237

    Open questions at the time
    • Molecular trigger linking filament state to MTOR signaling not defined
    • Causal vs. correlative role of filaments in neuroprotection partly inferred
  16. 2025 High

    Resolved how the S160del neurodevelopmental variant acts, showing it independently disrupts Bateman-domain dimerization (and thus filament assembly) and GTP allostery, separating the two regulatory functions structurally.

    Evidence Cryo-EM of S160del, Xenopus tropicalis expression, purine metabolomics, somitogenesis phenotyping, and high-affinity ligand rescue

    PMID:41343675

    Open questions at the time
    • Mapping of which clinical features arise from filament loss vs. allosteric loss incomplete
    • Therapeutic correction of allostery not achieved by the rescue ligand
  17. 2025 Medium

    Extended IMPDH2 signaling partnerships and viral exploitation, linking it to SRPK1/AKT-mTOR in T cells, c-Myc stability, and SARS-CoV-2 Nsp14-driven NF-κB activation.

    Evidence MS, Co-IP and colocalization for SRPK1; CETSA/Biacore/MST/Co-IP and ubiquitination assays for c-Myc; Nsp14 Co-IP with siRNA/inhibitor NF-κB readouts

    PMID:36177032 PMID:39008915 PMID:41213488

    Open questions at the time
    • Whether these effects require IMPDH2 catalysis or scaffolding is not consistently resolved
    • Direct vs. indirect nature of the c-Myc and SRPK1 regulatory links unclear
  18. 2026 Medium

    Identified an HSPA6–ROCK2 module that activates IMPDH2 via S416 phosphorylation to suppress DNA damage and confer radioresistance, adding a chaperone-kinase activating axis.

    Evidence Co-IP of HSPA6–IMPDH2 and ROCK2 recruitment, in vitro ROCK2 kinase assay on S416, enzymatic activity, and irradiated GBM mouse model

    PMID:42234559

    Open questions at the time
    • Interplay of S416 with S122 and Y233 phosphosites not integrated
    • How HSPA6 selectively recruits ROCK2 to IMPDH2 undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how the multiple regulatory layers—phosphorylation at S122/S416/Y233, lipid (PI3P) binding, ubiquitin turnover, filament assembly, and nuclear relocalization—are integrated into a single coherent control circuit, and which inputs dominate in specific tissues and disease states.
  • No unified model coordinating the distinct phosphosites and allosteric states
  • Y233 phosphorylation and PI3P regulation rest on a preprint not yet peer-reviewed
  • Tissue-specific dominance of each regulatory mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 1 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 1 R-HSA-73894 DNA Repair 1
Partners
ANKRD9FANCIHSPA6JOSD2PARP1PPIASRPK1USP5
Complex memberships
PPIA–SFA–IMPDH2 ternary complexPPP2CA–PPP2R1A–IMPDH2 (PP2A) complexrod/ring (RR) cytoophidia filaments

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structures of human IMPDH2 in active and inactive conformations define the mechanism of filament assembly: polymerization stabilizes conformations that make the enzyme less sensitive to feedback inhibition by GTP, explaining why assembly occurs when guanine nucleotide pool expansion is required. Filament-dependent allosteric regulation (tuning inhibitor sensitivity) distinguishes IMPDH2 from other metabolic filaments. Cryo-EM structural determination of IMPDH2 in multiple conformational states, correlated with enzymatic activity measurements eLife High 31999252
2017 IMPDH2 is an intracellular target of the cyclophilin A (PPIA)–sanglifehrin A (SFA) binary complex: the ternary PPIA-SFA-IMPDH2 complex forms through the CBS (cystathionine-β-synthase) domain of IMPDH2, does not inhibit IMPDH2 enzymatic activity, but modulates cell growth. The SFA complex is highly isoform-selective for IMPDH2 over IMPDH1. Affinity pulldown, co-immunoprecipitation, domain mapping (CBS domain), cell growth assays, isoform selectivity experiments Cell reports High 28076787
2019 ANKRD9 facilitates degradation of IMPDH2 (the rate-limiting GTP biosynthesis enzyme). Under basal conditions ANKRD9 is segregated from cytosolic IMPDH2 in vesicle-like structures; upon nutrient limitation, ANKRD9 loses its vesicular pattern and assembles with IMPDH2 into rod-like filaments where IMPDH2 is stable. Inhibition of IMPDH2 activity with ribavirin favors ANKRD9 binding to IMPDH2 rods; guanosine supplementation reverses this. The conserved Cys109-Cys110 motif in ANKRD9 is required for the vesicle-to-rods transition and for binding/regulation of IMPDH2. ANKRD9 knockdown increases IMPDH2 levels and prevents IMPDH2 rod formation upon nutrient limitation. Co-immunoprecipitation, fluorescence microscopy, subcellular fractionation, site-directed mutagenesis (Cys109/110), ANKRD9 knockdown and overexpression, guanosine rescue experiments The Journal of biological chemistry High 31337707
2023 Disease-associated point mutations in IMPDH2 linked to dystonia and neurodevelopmental disorders disrupt GTP-mediated allosteric inhibition of the enzyme. Cryo-EM structures of one IMPDH2 mutant reveal this regulatory defect arises from a shift in the conformational equilibrium toward a more active state, identifying gain-of-function dysregulation as the disease mechanism. Cryo-EM structural determination of mutant IMPDH2, enzymatic activity assays measuring GTP inhibition, patient variant identification The Journal of biological chemistry High 37414152
2024 IMPDH2 serine 122 (S122) is phosphorylated by CDK1; this modification attenuates IMPDH2 catalytic activity for IMP oxidation and represses its allosteric modulation by purine nucleotides. FGFR signaling activation triggers IMPDH2-S122 dephosphorylation mediated by protein phosphatase 2A (PP2A); this is dependent on FGFR3-mediated phosphorylation of PPP2R1A at Y261, leading to formation of a PPP2CA–PPP2R1A–IMPDH2 complex. Dephosphorylation at S122 activates IMPDH2, promotes guanine nucleotide synthesis, facilitates S-phase completion and cell proliferation. In vitro kinase assay (CDK1), phosphoproteomics, co-immunoprecipitation (PP2A complex), site-directed mutagenesis (S122), enzymatic activity assays, FGFR signaling manipulation Cell reports High 39739531
2024 IMPDH2 is enriched on chromatin in triple-negative breast cancer (TNBC). On chromatin, IMPDH2 interacts with PARP1 and modulates PARP1 activity by controlling the nuclear availability of NAD+, fine-tuning the DNA damage response. IMPDH2 repression leads to DNA damage accumulation; when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Chromatin fractionation, co-immunoprecipitation (IMPDH2-PARP1), NAD+ measurement in nuclear fractions, IMPDH2 knockdown/nuclear restriction experiments, DNA damage assays Nature communications High 39532854
2025 USP5 (ubiquitin-specific protease 5) binds IMPDH2 through its N-terminal cryptic ZnF-UBP and ZnF-UBP domains interacting with IMPDH2 residues 251–514, and removes K48-linked ubiquitin chains from IMPDH2, preventing ubiquitin-mediated proteasomal degradation and stabilizing IMPDH2 protein levels. Co-immunoprecipitation, domain mapping, ubiquitination assay, USP5 knockdown/overexpression, proteasome inhibitor experiments Oncogene Medium 40164869
2024 JOSD2 (a deubiquitinating enzyme) binds the C-terminal domain of IMPDH2 and preferentially cleaves K63-linked polyubiquitin chains at the K134 site of IMPDH2, suppressing IMPDH2 activity and preventing activation of NF-κB signaling and inflammation in macrophages. JOSD2 deficiency exacerbates colitis through enhanced IMPDH2-mediated NF-κB activation. Co-immunoprecipitation, in vitro deubiquitination assay (K63 chain specificity, K134 site identification), myeloid-specific JOSD2 knockout mice, NF-κB reporter assays Acta pharmaceutica Sinica. B Medium 40177575
2022 SARS-CoV-2 Nsp14 protein physically interacts with IMPDH2, and IMPDH2 knockdown or chemical inhibition abolishes Nsp14-mediated NF-κB activation and downstream cytokine (IL-6, IL-8) induction, demonstrating that IMPDH2 is required for Nsp14-driven NF-κB signaling and is exploited for viral replication. Co-immunoprecipitation (Nsp14–IMPDH2 interaction), siRNA knockdown of IMPDH2, NF-κB reporter assays, IMPDH2 inhibitors (ribavirin, mycophenolic acid), viral replication assays Frontiers in immunology Medium 36177032
2015 Microinjection of affinity-purified anti-IMPDH2 antibodies into live COS-7 cells caused disassembly of rod/ring (RR) structures, demonstrating that IMPDH2 is a major structural component and essential building block of cytoplasmic RR structures. RR structures are primarily stationary and stable in live cells. GFP-tagged IMPDH2 confirmed these findings independently. Microinjection of anti-IMPDH2 antibodies in live cells, live-cell fluorescence microscopy, GFP-IMPDH2 transfection, time-lapse imaging Cell & bioscience Medium 25601894
2015 Conditional deletion of Impdh2 in early neural crest cells (using Wnt1-Cre) produces highly penetrant intestinal aganglionosis, agenesis of craniofacial skeleton, and cardiac outflow tract/great vessel malformations, establishing that IMPDH2-mediated guanine nucleotide synthesis is essential for enteric nervous system development and other neural crest derivatives. Conditional knockout mouse (Wnt1-Cre × Impdh2-flox), Rosa26 reporter lineage tracing, histological and developmental analysis Developmental biology High 26546974
2020 IMPDH2 expression is necessary for activation of de novo GTP biosynthesis in glioblastoma; increased IMPDH2 enhances RNA polymerase I and III transcription, directly linking GTP metabolism to anabolic capacity and nucleolar enlargement. IMPDH2 knockdown/overexpression, GTP level measurement, RNA polymerase I/III activity assays, nucleolar size analysis Journal of biochemistry Medium 32702086
2023 FANCI directly binds IMPDH2 (by co-immunoprecipitation) and decreases IMPDH2 degradation; overexpression of IMPDH2 reverses the inhibitory effects of FANCI knockdown on lung adenocarcinoma cell proliferation via MEK/ERK/MMPs signaling activation. Co-immunoprecipitation, immunofluorescence co-localization, FANCI knockdown, IMPDH2 overexpression rescue, western blotting of MEK/ERK/MMP pathway OncoTargets and therapy Medium 32021289
2015 IMPDH2 and CTPS co-assemble into cytoplasmic rod/ring (RR) structures in a cell-type- and induction-dependent manner. Ribavirin and mycophenolic acid (MPA) treatments induce exclusively IMPDH2-based RR, while DON treatment produces mixed IMPDH2/CTPS RR. Assembly composition is determined by which biosynthetic pathway is inhibited. Immunofluorescence microscopy, drug treatments (ribavirin, MPA, DON), HA-tagged CTPS1 transfection, quantification of RR composition across cell lines Journal of genetics and genomics Medium 26165495
2024 In mouse models of AMPD2 deficiency, neurodegeneration-resistant brain regions accumulate micron-sized IMPDH2 filaments while the vulnerable hippocampal dentate gyrus shows barely detectable filaments. Blocking IMPDH2 polymerization using a dominant-negative IMPDH2 variant impairs growth of AMPD2-deficient neural progenitor cells, suggesting IMPDH2 filament assembly protects against GTP deprivation-induced neurodegeneration. Mouse knockout model (AMPD2 deficiency), immunofluorescence for IMPDH2 filaments, dominant-negative IMPDH2 variant expression in human neural progenitor cells, GTP level measurement EMBO reports Medium 39075237
2023 EBV EBNA2 and MYC (but not LMP1) induce IMPDH2 gene expression during primary B cell infection, leading to nucleolar hypertrophy. IMPDH2 induction and nucleolar enlargement are required for EBV-driven growth transformation of primary B cells, as inhibition by mycophenolic acid (MPA) blocks transformation. RNA-seq (IMPDH2 induction kinetics), EBNA2/LMP1 knockout EBV viruses, MPA pharmacological inhibition, electron microscopy of nucleolar size, mouse xenograft model with oral MMF Microbiology spectrum Medium 37409959
2025 IMPDH2 interacts with SRPK1 in CD4+ T cells (confirmed by mass spectrometry, co-immunoprecipitation, and confocal colocalization); IMPDH2 regulates SRPK1 expression, which subsequently activates the AKT/mTOR signaling pathway to promote CD4+ T cell proliferation and suppress apoptosis in myasthenia gravis. Mass spectrometry, co-immunoprecipitation, confocal fluorescence microscopy, IMPDH2 knockdown/overexpression, western blotting of AKT/mTOR pathway, flow cytometry Clinical immunology Medium 41213488
2020 Shikonin is a competitive inhibitor of IMPDH2 (Lineweaver-Burk plot), directly interacts with IMPDH2 protein (thermal shift assay and fluorescence quenching), and its anti-proliferative effects in TNBC cells are rescued by exogenous guanosine supplementation, confirming on-target mechanism through GTP biosynthesis inhibition. Enzymatic inhibition assays (Lineweaver-Burk), thermal shift assay, fluorescence quenching, molecular docking, guanosine rescue in cell proliferation assays, IMPDH2 knockdown Phytotherapy research Medium 32779300
2010 The IMPDH2 allozyme Phe263 has decreased enzymatic activity primarily due to decreased protein quantity caused by accelerated protein degradation, as supported by X-ray crystal structure analysis of IMPDH2. A promoter SNP (G>C IVS1-93) is associated with decreased mRNA quantity, possibly through altered transcription. Resequencing, allozyme functional assays, protein degradation experiments, X-ray crystal structure of IMPDH2, real-time PCR for mRNA quantification British journal of pharmacology Medium 20718729
2009 A promoter SNP in IMPDH2 (c.-95T>G) disrupts a cAMP response element (CRE) binding site, leading to a 55–65% decrease in IMPDH2 transcriptional activity as measured by luciferase reporter assays in HEK293 and Jurkat cells. Luciferase reporter gene assays with IMPDH2 promoter constructs (wild-type vs. mutant) transfected into HEK293 and Jurkat cell lines Genetic testing and molecular biomarkers Medium 19810816
2024 IMPDH2 cytoophidia (filaments) form in mouse oocytes in vivo during growth and in vitro upon IMPDH inhibition with MPA. In granulosa cells, cytoophidia form after the LH surge coinciding with reduced IMPDH2 protein expression and resumption of oocyte meiosis. MPA-induced cytoophidium formation in cumulus cells triggers meiosis resumption in enclosed oocytes via the MTOR pathway; guanosine supplementation prevents this, linking IMPDH2 filament formation to regulation of oocyte meiotic competence. Immunofluorescence in mouse ovarian sections, MPA treatment of cumulus-oocyte complexes (COCs), LH surge induction, guanosine rescue, MTOR pathway inhibition, meiotic resumption assay Frontiers in cell and developmental biology Medium 34124077
2025 ALK and SRC kinases phosphorylate IMPDH2 at tyrosine 233 (Y233) within the Bateman domain, and this phosphorylation is essential for IMPDH2 enzymatic activity. Phosphoinositide-3-phosphate (PI3P) selectively binds to and inhibits IMPDH2 but not IMPDH1, revealing an isoform-specific lipid-mediated regulatory mechanism. Peptide-based mutagenesis, in vitro enzymatic assays, PI3P binding assay, kinase activity assays (ALK, SRC), isoform comparison (IMPDH1 vs IMPDH2) bioRxivpreprint Low
2024 Impdh2 deletion in mouse myeloid lineage cells (LysM-Cre conditional KO) reduces osteoclast number and impairs osteoclast differentiation marker gene expression (Nfatc1, Ctsk, Calcr, Acp5, Dcstamp, Atp6v0d2), with genome-wide analysis showing impairment of mitochondrial biogenesis and oxidative phosphorylation in Impdh2-deficient osteoclasts. Deletion alleviates ovariectomy-induced bone loss. Myeloid-specific conditional KO (Impdh2-LysM-Cre), histomorphometric analysis, qPCR/western blot, genome-wide transcriptomic analysis, ovariectomy mouse model Biochemical and biophysical research communications Medium 38959733
2024 Vitexicarpin directly binds IMPDH2 (confirmed by CETSA, Biacore, MST) and promotes c-Myc ubiquitination by disrupting the protein-protein interaction between IMPDH2 and c-Myc, thereby inhibiting EMT in colorectal cancer. Co-IP confirmed a direct IMPDH2–c-Myc interaction. CETSA, label-free quantitative proteomics, Biacore, Co-IP, MST, ubiquitination assay, molecular docking, IMPDH2 overexpression/knockdown Phytomedicine Medium 39008915
2026 HSPA6 interacts with IMPDH2 and activates it by recruiting ROCK2 to phosphorylate IMPDH2 at serine 416 (S416), thereby promoting GTP synthesis, reducing DNA damage, and enhancing radioresistance of glioblastoma stem cells. Co-immunoprecipitation (HSPA6–IMPDH2, ROCK2 recruitment), in vitro kinase assay (ROCK2 phosphorylation of IMPDH2 S416), enzymatic activity assays, IMPDH2 knockdown/inhibition with irradiation, mouse GBM model Cell reports Medium 42234559
2025 IMPDH2 S160del mutant (neurodevelopmental disorder-associated) disrupts in vivo IMPDH2 filament assembly in Xenopus tropicalis by destabilizing dimerization of regulatory Bateman domains, as shown by cryo-EM structures. S160del expression disrupts purine pools and somite organization. Restoring Bateman domain dimerization with a high-affinity ligand rescues filament formation but does not restore GTP inhibition sensitivity, indicating S160del disrupts both filament assembly and allosteric regulation independently. Cryo-EM structure of S160del mutant, Xenopus tropicalis expression (WT vs. S160del), metabolomics (purine pools), developmental phenotyping (somitogenesis), filament visualization, high-affinity ligand rescue Proceedings of the National Academy of Sciences of the United States of America High 41343675
2024 IMPDH2 forms localized spots (not diffuse filaments) predominantly at branching sites and distal ends of astrocyte stem processes in adult mouse hippocampus and primary astrocyte cultures, suggesting a role in site-specific GTP availability regulation at specialized astrocyte nodes. Immunofluorescence microscopy of adult mouse hippocampal sections and primary astrocyte cultures, quantitative distribution analysis Genes to cells Low 38009721
2024 In Xenopus tropicalis tadpoles, inhibition of IMPDH2 impairs tail regeneration and reduces cell proliferation in regenerating tissue. Endogenous and GFP-tagged IMPDH2 robustly assembles into filaments throughout the tadpole tail, and the regenerating tail creates a sensitized condition for filament formation compared to non-regenerating tissue. IMPDH2 inhibitor treatment during tail regeneration, proliferation assay (EdU), endogenous filament immunofluorescence, GFP-IMPDH2 fusion live imaging in tadpole tail bioRxivpreprint Low 39131357
2024 Impdh2 conditional knockout in adipocyte precursor cells (APCs) reduces white adipose tissue expansion under high-fat diet by limiting mitotic clonal expansion (MCE) during adipogenesis. XMP (xanthosine monophosphate, an IMPDH2 product) enhances adipogenic potential; exogenous XMP rescues the reduced adipogenic ability of Impdh2-deficient APCs, mechanistically linking Impdh2 activity to APC proliferation through nucleotide provision. APC-specific conditional Impdh2 knockout, high-fat diet model, XMP supplementation rescue, adipogenesis assays, energy expenditure measurement Biochemical and biophysical research communications Medium 38692012
2023 B7-H3 (CD276) co-immunoprecipitates with IMPDH2 in lung cancer cells; this complex protects cancer cells from oxidative stress triggered by chemotherapy, promoting cell survival. Loss of B7-H3 promotes 3D spheroid expansion in an IMPDH2-dependent manner, establishing a functional interaction between B7-H3 and IMPDH2 in metabolic homeostasis. Co-immunoprecipitation (B7-H3–IMPDH2), oxidative stress assays, B7-H3 knockdown with 3D spheroid growth, IMPDH2-dependent rescue experiments Cancers Low 37444640

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways. Journal of experimental & clinical cancer research : CR 177 30518405
2020 Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation. eLife 82 31999252
2017 IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex. Cell reports 47 28076787
2015 Assembly of IMPDH2-based, CTPS-based, and mixed rod/ring structures is dependent on cell type and conditions of induction. Journal of genetics and genomics = Yi chuan xue bao 45 26165495
2020 GTP metabolic reprogramming by IMPDH2: unlocking cancer cells' fuelling mechanism. Journal of biochemistry 39 32702086
2009 Identification of IMPDH2 as a tumor-associated antigen in colorectal cancer using immunoproteomics analysis. International journal of colorectal disease 38 19597826
2020 Shikonin is a novel and selective IMPDH2 inhibitor that target triple-negative breast cancer. Phytotherapy research : PTR 36 32779300
2005 Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells. The FEBS journal 35 15670151
2015 Microinjection of specific anti-IMPDH2 antibodies induces disassembly of cytoplasmic rods/rings that are primarily stationary and stable structures. Cell & bioscience 32 25601894
2006 ZNRD1 mediates resistance of gastric cancer cells to methotrexate by regulation of IMPDH2 and Bcl-2. Biochemistry and cell biology = Biochimie et biologie cellulaire 32 16609701
2014 Enhanced expression of IMPDH2 promotes metastasis and advanced tumor progression in patients with prostate cancer. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 31 24659377
2010 Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics. British journal of pharmacology 31 20718729
2008 Expression of IMPDH1 and IMPDH2 after transplantation and initiation of immunosuppression. Transplantation 30 18192912
2021 Circular RNA circPFKP promotes cell proliferation by activating IMPDH2 in prostate cancer. Cancer letters 28 34673127
2014 Elevated expression of IMPDH2 is associated with progression of kidney and bladder cancer. Medical oncology (Northwood, London, England) 26 25465060
2022 SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling. Frontiers in immunology 25 36177032
2021 IMPDH2: a new gene associated with dominant juvenile-onset dystonia-tremor disorder. European journal of human genetics : EJHG 25 34305140
2019 ANKRD9 is a metabolically-controlled regulator of IMPDH2 abundance and macro-assembly. The Journal of biological chemistry 24 31337707
1993 Chromosomal localization and structure of the human type II IMP dehydrogenase gene (IMPDH2). Genomics 24 8098009
2024 Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer. Journal of translational medicine 20 38310229
2009 Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug metabolism and pharmacokinetics 20 20045992
2020 FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway. OncoTargets and therapy 19 32021289
2015 Neural crest requires Impdh2 for development of the enteric nervous system, great vessels, and craniofacial skeleton. Developmental biology 19 26546974
2014 IMPDH2 mediate radioresistance and chemoresistance in osteosarcoma cells. European review for medical and pharmacological sciences 19 25392102
2023 Berberrubine is a novel and selective IMPDH2 inhibitor that impairs the growth of colorectal cancer. Biochemical pharmacology 16 37871880
2007 Real-time PCR determination of IMPDH1 and IMPDH2 expression in blood cells. Clinical chemistry 16 17463174
2022 Genistein promotes apoptosis of lung cancer cells through the IMPDH2/AKT1 pathway. American journal of translational research 15 36398246
2020 IMPDH2 promotes cell proliferation and epithelial-mesenchymal transition of non-small cell lung cancer by activating the Wnt/β-catenin signaling pathway. Oncology letters 15 32963625
2024 Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity. Nature communications 14 39532854
2025 Inosine monophosphate dehydrogenase 2 (IMPDH2) modulates response to therapy and chemo-resistance in triple negative breast cancer. Scientific reports 13 39774345
2023 Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation. The Journal of biological chemistry 13 37414152
2022 A recombinant scFv antibody-based fusion protein that targets EGFR associated with IMPDH2 downregulation and its drug conjugate show therapeutic efficacy against esophageal cancer. Drug delivery 12 35416106
2018 Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil. Mutation research. Genetic toxicology and environmental mutagenesis 12 30442353
2011 Lymphocyte counts in kidney allograft recipients are associated with IMPDH2 3757T>C gene polymorphism. Transplantation proceedings 12 21996196
2009 IMPDH2 genetic polymorphism: a promoter single-nucleotide polymorphism disrupts a cyclic adenosine monophosphate responsive element. Genetic testing and molecular biomarkers 11 19810816
2023 Growth Transformation of B Cells by Epstein-Barr Virus Requires IMPDH2 Induction and Nucleolar Hypertrophy. Microbiology spectrum 10 37409959
2021 Coordinated Formation of IMPDH2 Cytoophidium in Mouse Oocytes and Granulosa Cells. Frontiers in cell and developmental biology 9 34124077
2023 Single-cell RNA sequencing in double-hit lymphoma: IMPDH2 induces the progression of lymphoma by activating the PI3K/AKT/mTOR signaling pathway. International immunopharmacology 8 37907047
2024 Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages. Acta pharmaceutica Sinica. B 7 40177575
2021 Actein antagonizes colorectal cancer through blocking PI3K/Akt pathways by downregulating IMPDH2. Anti-cancer drugs 7 33929996
2008 Interpopulation variation frequency of human inosine 5'-monophosphate dehydrogenase type II (IMPDH2) genetic polymorphisms. Genetic testing 7 18976158
2024 IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth. Cell reports 6 39739531
2019 Design, synthesis and biological evaluation of Helicobacter pylori inosine 5'-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2. Bioorganic chemistry 6 30974298
2023 Rare variants in IMPDH2 cause autosomal dominant dystonia in Chinese population. Journal of neurology 5 36648520
2010 Inter-ethnic variability of three functional polymorphisms affecting the IMPDH2 gene. Molecular biology reports 5 21181270
2025 USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression. Oncogene 4 40164869
2024 Vitexicarpin suppresses malignant progression of colorectal cancer through affecting c-Myc ubiquitination by targeting IMPDH2. Phytomedicine : international journal of phytotherapy and phytopharmacology 4 39008915
2024 IMPDH2 suppression impedes cell proliferation by instigating cell cycle arrest and stimulates apoptosis in pediatric hepatoblastoma. Journal of cancer research and clinical oncology 4 39085725
2025 IMPDH2's Central Role in Cellular Growth and Diseases: A Potential Therapeutic Target. Cell proliferation 3 40251939
2024 IMPDH2 Positively Impacts the Proliferation Potential of Hepatoblastoma Cells by Activating JunB Signaling Pathway. Current molecular pharmacology 3 38676510
2024 Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy. Cancer gene therapy 3 38871858
2024 Impdh2 deficiency suppresses osteoclastogenesis through mitochondrial oxidative phosphorylation and alleviates ovariectomy-induced osteoporosis. Biochemical and biophysical research communications 3 38959733
2024 IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency. EMBO reports 3 39075237
2023 Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure. bioRxiv : the preprint server for biology 3 36993700
2023 B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival. Cancers 3 37444640
2024 Deletion of Impdh2 in adipocyte precursors limits the expansion of white adipose tissue and enhances metabolic health with overnutrition. Biochemical and biophysical research communications 2 38692012
2024 Appendage regeneration requires IMPDH2 and creates a sensitized environment for enzyme filament formation. bioRxiv : the preprint server for biology 2 39131357
2023 IMPDH2 forms spots at branching sites and distal ends of astrocyte stem processes. Genes to cells : devoted to molecular & cellular mechanisms 2 38009721
2026 Glucose Induces DNMT1/IMPDH2-Dependent Metabolic Memory in Endothelial Cells Upon Reprograming Nucleotide Metabolism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 41445454
2026 Integrated screens reveal that guanine nucleotide depletion, which is irreversible via targeting IMPDH2, inhibits pancreatic cancer and potentiates KRAS inhibition. Gut 1 41494804
2024 Corrigendum to: IMPDH2 Positively Impacts the Proliferation Potential of Hepatoblastoma Cells by Activating JunB Signaling Pathway. Current molecular pharmacology 1 40492554
2023 Genetic analysis of IMPDH2 gene in Taiwanese patients with isolated or combined dystonia. Parkinsonism & related disorders 1 36657279
2026 ANKRD9 negatively regulates chicken myogenesis through ubiquitin-mediated regulation of IMPDH2. Poultry science 0 41691811
2026 tRF-1432 orchestrates RBMS1-IMPDH2 regulatory control to drive purine-dependent chemoresistance in breast cancer. Cancer letters 0 41791644
2026 HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells. Cell reports 0 42234559
2025 Domain-specific AI segmentation of IMPDH2 rod/ring structures in mouse embryonic stem cells. BMC biology 0 40350411
2025 An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somitogenesis. bioRxiv : the preprint server for biology 0 40654686
2025 IMPDH2 facilitates CD4+ T cell activation through AKT/mTOR pathway by upregulating SRPK1 in myasthenia gravis. Clinical immunology (Orlando, Fla.) 0 41213488
2025 An IMPDH2 variant associated with neurodevelopmental disorder disrupts purine biosynthesis and somite organization. Proceedings of the National Academy of Sciences of the United States of America 0 41343675
2025 DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer. Acta pharmaceutica Sinica. B 0 41584327
2024 IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency. bioRxiv : the preprint server for biology 0 38328116
2024 Inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C (rs11706052) and 12-month evolution of the graft function in renal transplant recipients on mycophenolate-based immunosuppression. The pharmacogenomics journal 0 38769303

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