Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2; EC 1.1.1.205) is the ubiquitous, proliferation-associated isozyme of IMP dehydrogenase. It catalyzes the NAD+-dependent oxidation of inosine-5'-monophosphate (IMP) to xanthosine-5'-monophosphate (XMP) (IMP + NAD+ + H2O -> XMP + NADH + H+), the first committed and rate-limiting step in de novo guanine-nucleotide biosynthesis; GMP synthase then aminates XMP to GMP. The enzyme is a homotetramer whose regulatory Bateman/CBS-domain subdomain (two CBS domains) binds single-stranded nucleic acids and mediates reversible polymerization into micron-scale filaments ("rods and rings"/cytoophidia) under guanine-nucleotide depletion. IMPDH2 is predominantly cytosolic. As the constitutively inducible isoform enriched in proliferating and neoplastic cells, it is the principal target of the immunosuppressant mycophenolic acid (mycophenolate mofetil) and of the antiviral ribavirin. Loss-of-function and gain-of-function variants cause a neurodevelopmental disorder with dystonia (IMPDH2-related dystonia).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that IMPDH2 is active in the cytoplasm. Correct but broad; the more precise experimentally supported location is the cytosol. Reason: IMPDH2 is a soluble cytoplasmic/cytosolic enzyme. The cytoplasm annotation is correct at the general level and consistent with the IBA panel across orthologs. The finer cytosol term (GO:0005829) is also annotated and captured as the core location. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0003938 IMP dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of IMP dehydrogenase activity, the defining molecular function of the IMPDH/GMPR family. This is the core function of IMPDH2. Reason: Directly supported by experimental characterization of the purified human recombinant enzyme and by pan-family conservation. This is the committed, rate-limiting catalytic step of de novo guanine-nucleotide synthesis. Supporting Evidence: PMID:7903306 Both recombinant isoforms were PMID:1969416 the rate-limiting enzyme of de novo GTP |
| GO:0006183 GTP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that IMPDH2 participates in GTP biosynthesis. IMPDH catalyzes the committed step of the de novo guanine-nucleotide branch that feeds GMP -> GDP -> GTP. Reason: IMPDH is standardly described as the rate-limiting enzyme of de novo GTP/guanine nucleotide biosynthesis; the enzyme's product XMP is aminated to GMP and phosphorylated to GTP. The IBA annotation to the guanine-nucleotide pathway is appropriate. Supporting Evidence: PMID:1969416 the rate-limiting enzyme of de novo GTP PMID:14766016 IMPDH) is the rate-limiting enzyme in |
| GO:0000166 nucleotide binding | IEA GO_REF:0000104 | ACCEPT | Summary: Electronic (UniRule) inference of nucleotide binding. IMPDH2 binds the substrate IMP and the cosubstrate NAD+, both nucleotides, at defined active-site residues. Reason: Consistent with the documented IMP and NAD(+) binding sites and with the catalytic mechanism. The term is generic (a parent of substrate/cofactor binding) but not incorrect; treated as supporting rather than a core informative MF term. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt XMP biosynthesis via de novo pathway |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation of the root-level catalytic activity term. Reason: Correct but maximally uninformative; it is a high-level parent of the specific and well-supported GO:0003938 IMP dehydrogenase activity, which is annotated multiply. Retained as an IEA parent but flagged as over-annotated rather than a useful function. Supporting Evidence: PMID:7903306 Both recombinant isoforms were |
| GO:0003938 IMP dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/UniRule, EC 1.1.1.205, RHEA:11708) inference of IMP dehydrogenase activity, the core molecular function. Reason: The mapping to EC 1.1.1.205 / RHEA:11708 (IMP + NAD+ + H2O = XMP + NADH + H+) is exactly correct and corroborated by the experimental annotations. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt XMP biosynthesis via de novo pathway |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (UniRule/SubCell SL-0191) inference of nuclear localization, mirroring the experimental nuclear localization reported for IMPDH. Reason: A nuclear pool of IMPDH has been observed and is linked to the moonlighting single-stranded nucleic-acid-binding activity of the CBS subdomain, but the enzyme's catalytic role is overwhelmingly cytosolic. Retained as a genuine but non-core secondary location. Supporting Evidence: PMID:14766016 IMPDH is found in the nucleus of human cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule/SubCell SL-0086) inference of cytoplasmic localization. Reason: Correct; IMPDH2 is a soluble cytoplasmic enzyme. Redundant with the IBA and IDA cytoplasm/cytosol annotations. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (SubCell SL-0091) inference of cytosolic localization, the principal site of IMPDH2 catalysis. Reason: Cytosol is the core, experimentally supported location (IDA in PMID:31337707 and HPA). This IEA is fully consistent. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0006164 purine nucleotide biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to purine nucleotide biosynthesis. Reason: Correct but broad. IMPDH2 acts in the purine (specifically guanine) nucleotide biosynthetic pathway; the finer terms GO:0006177 (GMP biosynthetic process) and GO:0097294 ('de novo' XMP biosynthetic process) capture the precise step and are also annotated. Retained as an accurate parent-level process. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt XMP biosynthesis via de novo pathway |
| GO:0006177 GMP biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule) inference that IMPDH2 acts in GMP biosynthesis. IMPDH catalyzes the committed step (IMP -> XMP) that immediately precedes GMP synthase's conversion of XMP to GMP. Reason: IMPDH2 is the rate-limiting entry point of the GMP (guanine nucleotide) biosynthetic branch; annotation to GMP biosynthetic process is the standard and appropriate pathway-level BP for this enzyme. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt XMP biosynthesis via de novo pathway PMID:14766016 IMPDH) is the rate-limiting enzyme in |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation to the parent oxidoreductase activity term. Reason: Correct (IMPDH is an NAD-dependent oxidoreductase) but a high-level parent of the specific GO:0003938 IMP dehydrogenase activity, which is annotated multiply. Flagged as over-annotated relative to the informative child term. Supporting Evidence: PMID:7903306 Xanthosine 5'-monophosphate and NADH inhibited the two isoforms |
| GO:0046872 metal ion binding | IEA GO_REF:0000104 | ACCEPT | Summary: Electronic (UniRule) inference of metal ion binding, corresponding to the documented monovalent cation (K+) requirement and multiple potassium binding sites. Reason: IMPDH activity depends on a monovalent cation cofactor (K+), and UniProt lists several K(+) binding residues shared between tetrameric partners. The metal-ion-binding annotation is structurally supported, though the finer specificity is potassium ion binding. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt ligand shared between two tetrameric |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Protein binding IPI from a proteome-scale binary interactome (Y2H) screen (APIP, CPLANE2). Bare protein binding is uninformative about IMPDH2's function. Reason: Per curation policy the generic 'protein binding' term conveys no functional information and this is a high-throughput interactome IPI, not a characterized functional partnership. Not removed (it is a valid experimental IPI), but marked as over-annotated. Supporting Evidence: PMID:25416956 a systematic map of ?14,000 high-quality human |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Protein binding IPI from the HuRI all-by-all binary interactome map (multiple partners incl. IMPDH1, STAT3, TRAF2). Uninformative bare protein binding. Reason: Generic 'protein binding' from a systematic proteome-wide two-hybrid map; no specific functional consequence for IMPDH2 is established. Retained as a valid IPI but flagged over-annotated. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment... | MARK AS OVER ANNOTATED | Summary: Protein binding IPI from a HaloTag-enrichment mass-spectrometry adipocyte interactome screen (STAT3). Uninformative bare protein binding. Reason: High-throughput affinity-MS interactome derived; the generic term is uninformative about IMPDH2 function. Kept as a valid IPI but marked over-annotated. Supporting Evidence: PMID:38884001 map protein complex interaction networks in adipocytes |
| GO:0097294 'de novo' XMP biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara ortholog-transfer annotation to de novo XMP biosynthesis, the most precise process description of the reaction IMPDH2 catalyzes (IMP -> XMP). Reason: This is the exact biological process for the enzyme's reaction; UniProt records the pathway as XMP biosynthesis via the de novo pathway. This is the single most precise BP term in the set. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt XMP biosynthesis via de novo pathway |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (Human Protein Atlas) localization of IMPDH2 to the cytosol. Reason: Consistent with the primary, experimentally supported cytosolic localization of the enzyme and with the PMID:31337707 IDA. Core location. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0003938 IMP dehydrogenase activity | EXP PMID:7763314 Recombinant human inosine monophosphate dehydrogenase type I... | ACCEPT | Summary: Experimental characterization of purified recombinant human type II IMPDH enzyme, including substrate kinetics and inhibitor (mycophenolic acid, mizoribine monophosphate) binding. Establishes the core catalytic activity. Reason: Direct biochemical assay of the human type II (IMPDH2) enzyme purified from E. coli; mycophenolic acid inhibits with Ki values of 11 and 6 nM (type I/II). This is strong experimental support for GO:0003938 and this is the gene's core function. Supporting Evidence: PMID:7763314 uncompetitively by mycophenolic acid with Ki values of 11 and 6 nM PMID:7763314 IMPDH is an important |
| GO:0003938 IMP dehydrogenase activity | IDA PMID:7903306 Characterization of human type I and type II IMP dehydrogena... | ACCEPT | Summary: Direct assay of purified recombinant human type II IMPDH; tetrameric, Km(IMP) 9.3 uM, Km(NAD) 32 uM, product-inhibited by XMP and NADH, Ordered Bi Bi mechanism. Core catalytic activity. Reason: Quantitative kinetic characterization of the human type II enzyme; unambiguous experimental support for IMP dehydrogenase activity, the core molecular function. Supporting Evidence: PMID:7903306 9.3 microM, respectively, for IMP, and 46 and 32 microM PMID:7903306 inhibited the type II enzyme with a 4.8-fold lower K than the type I |
| GO:0006183 GTP biosynthetic process | IDA PMID:7903306 Characterization of human type I and type II IMP dehydrogena... | ACCEPT | Summary: The enzyme characterized by direct assay is the rate-limiting step feeding de novo guanine-nucleotide (GTP) biosynthesis. Reason: The catalyzed IMP -> XMP reaction is the committed step of the pathway leading to GMP and then GTP; product inhibition by XMP/NADH and the isozyme kinetics documented in this paper place IMPDH2 in de novo guanine-nucleotide biosynthesis. Supporting Evidence: PMID:7903306 Xanthosine 5'-monophosphate and NADH inhibited the two isoforms PMID:1969416 the rate-limiting enzyme of de novo GTP |
| GO:0005829 cytosol | IDA PMID:31337707 ANKRD9 is a metabolically-controlled regulator of IMPDH2 abu... | ACCEPT | Summary: Direct evidence that IMPDH2 is cytosolic; under basal (nutrient-replete) conditions it is segregated from ANKRD9, and upon nutrient limitation it assembles into rodlike filaments. Reason: Experimental cytosolic localization; core location of the enzyme. Also documents the regulated macro-assembly (filament) behavior of IMPDH2. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 PMID:31337707 assembles with IMPDH2 into rodlike filaments |
| GO:0005515 protein binding | IPI PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | MARK AS OVER ANNOTATED | Summary: IPI recording the IMPDH2-CLOCK interaction (IMPDH2 is a CLOCK acetylation substrate). Bare protein binding is uninformative. Reason: The interaction with CLOCK is real and mechanistically interesting (circadian acetylation), but the generic 'protein binding' term conveys no function. Kept as a valid experimental IPI, flagged over-annotated; the biology is captured in the circadian-rhythm annotation and notes. Supporting Evidence: PMID:28985504 as acetylation substrates of CLOCK |
| GO:0007623 circadian rhythm | IDA PMID:28985504 CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenes... | KEEP AS NON CORE | Summary: IMPDH2 was identified as an acetylation substrate of the circadian acetyltransferase CLOCK, alongside NDUFA9, in a study of circadian ureagenesis. Reason: The evidence shows IMPDH2 is a target of circadian post-translational regulation (CLOCK-mediated acetylation), not that IMPDH2 is a core component of the circadian clock. This is a genuine regulatory context but peripheral to the enzyme's core metabolic function; retained as non-core. Supporting Evidence: PMID:28985504 as acetylation substrates of CLOCK PMID:28985504 acting as a rhythmic acetyl-transferase for metabolic |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Reactome pathway-membership annotation placing IMPDH2 in exocytosis of secretory granule lumen proteins (neutrophil degranulation), yielding an extracellular-region location. Reason: IMPDH2 is a soluble cytosolic enzyme with no signal peptide or secretion signal. Its presence in degranulation/secretory-granule datasets reflects abundant cytosolic protein carried along in neutrophil-granule proteomics rather than a bona fide extracellular functional location. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt the first committed and rate-limiting |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Reactome pathway-membership annotation (exocytosis of ficolin-rich granule lumen proteins) placing IMPDH2 in the extracellular region. Reason: As above, this derives from neutrophil-degranulation granule proteomics and does not represent a genuine secreted/extracellular function for this cytosolic enzyme. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt the first committed and rate-limiting |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Reactome neutrophil-degranulation pathway-membership annotation to secretory granule lumen. Reason: Reflects detection of the abundant cytosolic enzyme in granule proteomics, not a dedicated luminal secretory-granule localization. Over-annotation for a cytosolic metabolic enzyme. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt the first committed and rate-limiting |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Reactome neutrophil-degranulation pathway-membership annotation to ficolin-1-rich granule lumen. Reason: Same neutrophil-granule proteomics origin; a bystander localization rather than a functional site for the cytosolic IMPDH2 enzyme. Supporting Evidence: file:human/IMPDH2/IMPDH2-uniprot.txt the first committed and rate-limiting |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput membrane-proteome (NK-cell) mass-spectrometry detection of IMPDH2, yielding a generic membrane localization. Reason: The study itself notes that a large fraction of identified species are soluble proteins transiently associated with membranes; IMPDH2 has no transmembrane domain and is a cytosolic enzyme. The membrane annotation is a proteomic-contaminant/peripheral association, not a functional location. Supporting Evidence: PMID:19946888 transiently associated with membranes |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: High-throughput proteomic detection of IMPDH2 in B-cell exosomes. Reason: Abundant cytosolic proteins are routinely detected in whole-exosome proteomes; this does not establish a functional exosomal role for IMPDH2. Bystander/contaminant localization for a cytosolic enzyme. Supporting Evidence: PMID:20458337 identified 539 proteins, including known and not |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73794 | ACCEPT | Summary: Reactome annotation for the IMP + H2O + NAD+ to XMP + NADH + H+ reaction placing the IMPDH1,2 activity in the cytosol. Reason: Correct cytosolic localization tied directly to the catalyzed reaction; fully consistent with the core function and location. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9678749 | ACCEPT | Summary: Reactome annotation (IMPDH tetramers bind IMPDH inhibitors) placing IMPDH2 in the cytosol. Reason: Correct cytosolic localization; also reflects the tetrameric assembly and inhibitor (e.g. mycophenolic acid) binding that are hallmark features of the enzyme. Supporting Evidence: PMID:7763314 uncompetitively by mycophenolic acid with Ki values of 11 and 6 nM |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9748945 | ACCEPT | Summary: Reactome annotation (IMPDH tetramers dehydrogenate 6TIMP to 6TXMP, thiopurine metabolism) placing IMPDH2 in the cytosol. Reason: Correct cytosolic localization; captures the enzyme's ability to also dehydrogenate the thiopurine analog 6-thio-IMP, consistent with its IMP dehydrogenase activity. Supporting Evidence: PMID:31337707 Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 |
| GO:0005778 peroxisomal membrane | HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ... | MARK AS OVER ANNOTATED | Summary: High-throughput detection of IMPDH2 among proteins co-purifying with PEX14 complexes from peroxisomal membranes. Reason: IMPDH2 has no peroxisomal targeting signal and is a cytosolic enzyme; its appearance in a PEX14 pulldown/peroxisomal-membrane proteome reflects co-purification of an abundant cytosolic protein rather than genuine peroxisomal-membrane residency. Supporting Evidence: PMID:21525035 isolating native peroxisomal membrane |
| GO:0005634 nucleus | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | KEEP AS NON CORE | Summary: Direct evidence that IMPDH is present in the nucleus of human cells, consistent with its documented single-stranded nucleic-acid-binding activity mediated by the CBS subdomain. Reason: A nuclear pool of IMPDH is genuinely observed and linked to a moonlighting RNA/DNA-binding role of the Bateman/CBS subdomain. However, the enzyme's core catalytic function operates in the cytosol; the nuclear localization is a real but secondary, non-core feature. Supporting Evidence: PMID:14766016 IMPDH is found in the nucleus of human cells |
| GO:0005737 cytoplasm | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | ACCEPT | Summary: Direct evidence of cytoplasmic localization of IMPDH. Reason: Consistent with the soluble cytoplasmic/cytosolic nature of the enzyme; supports the core location alongside the cytosol annotations. Supporting Evidence: PMID:14766016 IMPDH is found in the nucleus of human cells |
| GO:0000166 nucleotide binding | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | ACCEPT | Summary: Direct-assay annotation of nucleotide binding. In this study IMPDH binds single-stranded nucleic acids with nanomolar affinity via the CBS subdomain; the enzyme also binds the IMP substrate and NAD+ cosubstrate. Reason: Nucleotide binding is genuine for IMPDH2 (substrate IMP, cosubstrate NAD, plus the nucleic-acid-binding CBS subdomain). The term is generic; the specific nucleic-acid-binding moonlighting activity is documented in the notes and treated as non-core. Supporting Evidence: PMID:14766016 bind single-stranded nucleic acids with nanomolar affinity via the |
| GO:0003938 IMP dehydrogenase activity | TAS PMID:1969416 Two distinct cDNAs for human IMP dehydrogenase. | ACCEPT | Summary: Traceable author statement that IMP dehydrogenase (EC 1.1.1.205) is the rate-limiting enzyme of de novo GTP biosynthesis; the paper reports the two distinct human cDNAs (type I=IMPDH1, type II=IMPDH2). Reason: Author-asserted, well-established identification of IMPDH2's catalytic identity and rate-limiting role; concordant with all other lines of evidence for the core function. Supporting Evidence: PMID:1969416 the rate-limiting enzyme of de novo GTP |
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Download this section (compressed HTML)Q: To what extent does the nuclear pool of IMPDH2 and its CBS-subdomain single-stranded nucleic-acid binding contribute to RNA/DNA metabolism in vivo, as opposed to being an in vitro/adventitious activity?
Q: What is the physiological role of reversible IMPDH2 filament assembly (rods and rings / cytoophidia) in tuning de novo GTP flux, and how do disease variants alter it?
Experiment: Structure-guided separation-of-function mutants that abolish CBS-subdomain nucleic-acid binding while preserving catalysis, to test the moonlighting nuclear role.
Experiment: Live-cell imaging of endogenously tagged IMPDH2 under guanine-nucleotide depletion and with disease-associated variants to quantify filament assembly kinetics and correlate with cellular GTP levels.
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