Existing Annotations Review

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

Core Functions

NAD+-dependent oxidation of IMP to XMP, the committed and rate-limiting step of de novo guanine-nucleotide biosynthesis, performed by the cytosolic IMPDH2 homotetramer.

Molecular Function:

IMP dehydrogenase activity

Directly Involved In:

GMP biosynthetic process purine nucleotide biosynthetic process

Cellular Locations:

cytosol

Supporting Evidence:

PMID:7903306
9.3 microM, respectively, for IMP, and 46 and 32 microM
PMID:1969416
the rate-limiting enzyme of de novo GTP
file:human/IMPDH2/IMPDH2-uniprot.txt
XMP biosynthesis via de novo pathway

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000104

Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:14766016

Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo.

PMID:1969416

Two distinct cDNAs for human IMP dehydrogenase.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:21525035

PEX14 is required for microtubule-based peroxisome motility in human cells.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28985504

CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.

PMID:31337707

ANKRD9 is a metabolically-controlled regulator of IMPDH2 abundance and macro-assembly.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:38884001

Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.

PMID:7763314

Recombinant human inosine monophosphate dehydrogenase type I and type II proteins. Purification and characterization of inhibitor binding.

PMID:7903306

Characterization of human type I and type II IMP dehydrogenases.

Reactome:R-HSA-6798748

Exocytosis of secretory granule lumen proteins

Reactome:R-HSA-6800434

Exocytosis of ficolin-rich granule lumen proteins

Reactome:R-HSA-73794

IMP + H2O + NAD+ => XMP + NADH + H+ [IMPDH1,2]

Reactome:R-HSA-9678749

IMPDH tetramers bind IMPDH inhibitors

Reactome:R-HSA-9748945

IMPDH tetramers dehydrogenate 6TIMP to 6TXMP

file:human/IMPDH2/IMPDH2-uniprot.txt

UniProtKB entry P12268 (IMPDH2_HUMAN)

Suggested Experiments

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.

📚 Additional Documentation

Notes

(IMPDH2-notes.md)

IMPDH2 (human, UniProtKB:P12268) — review notes

Summary of gene function

IMPDH2 is inosine-5'-monophosphate dehydrogenase 2 (EC 1.1.1.205), the ubiquitous,
proliferation-associated isozyme of IMP dehydrogenase. It catalyzes the NAD+-dependent
oxidation of IMP to xanthosine-5'-monophosphate (XMP):

IMP + NAD+ + H2O -> XMP + NADH + H+   (RHEA:11708)

This is the first committed and rate-limiting step of de novo guanine-nucleotide
biosynthesis; GMP synthase (GMPS) then aminates XMP to GMP, and downstream kinases give
GDP/GTP/dGTP. Because de novo GTP supply is tightly coupled to cell proliferation, IMPDH2
is a validated drug target.

Key established facts (with provenance)

Enzymatic activity / reaction. UniProt CATALYTIC ACTIVITY: "IMP + NAD(+) + H2O = XMP +
NADH + H(+)"; EC=1.1.1.205; PATHWAY: "Purine metabolism; XMP biosynthesis via de novo
pathway; XMP from IMP: step 1/1" [file:human/IMPDH2/IMPDH2-uniprot.txt].
Kinetics and isozyme comparison. Type II Km(IMP)=9.3 uM, Km(NAD)=32 uM; both type I and
II are tetramers; product-inhibited by XMP and NADH; MPA inhibits type II with ~4.8-fold
lower Ki than type I [PMID:7903306 "with Km values of 18 and / 9.3 microM, respectively,
for IMP, and 46 and 32 microM"; "Both recombinant isoforms were / tetramers"].
Inhibitor binding. Recombinant type I/II purified from E. coli; MPA is a potent
tight-binding uncompetitive inhibitor (Ki 11 and 6 nM); mizoribine-5'-monophosphate a
competitive inhibitor PMID:7763314.
Rate-limiting role in de novo GTP/guanine-nucleotide synthesis. "IMP dehydrogenase (EC
1.1.1.205), the rate-limiting enzyme of de novo GTP / biosynthesis" PMID:1969416;
"IMPDH is the rate-limiting enzyme in / the de novo biosynthesis of guanine nucleotides"
PMID:14766016.
Two isoforms / tissue distribution. Two distinct cDNAs (type I=IMPDH1, type II=IMPDH2),
84% identical, 514 residues; type I predominant in normal leukocytes, type II
predominates in tumor PMID:1969416.
CBS/Bateman subdomain and nucleic-acid binding. The catalytic domain carries a subdomain
of two CBS (cystathionine-beta-synthase) domains; human IMPDH isoforms bind
single-stranded nucleic acids with nanomolar affinity via this subdomain; IMPDH found in
the nucleus and binds RNA and DNA in vivo PMID:14766016. This is a secondary,
moonlighting activity, not the core catalytic function. UniProt features: CBS 1
(114–173), CBS 2 (179–237) [file:human/IMPDH2/IMPDH2-uniprot.txt].
Filament / macro-assembly ("rods and rings" / cytoophidia). IMPDH2 polymerizes into
filaments upon guanine-nucleotide depletion; UniProt: "Can form fiber-like subcellular
structures termed 'cytoophidia'"; ANKRD9 controls IMPDH2 abundance and macro-assembly
and drives its ubiquitin-dependent degradation [PMID:31337707; PMID:30293565].
Subcellular location. Cytosol is the principal, experimentally supported location
[PMID:31337707 IDA; HPA IDA GO_REF:0000052]. Also reported cytoplasm and nucleus
PMID:14766016.
Regulation / PTMs. Acetylated by CLOCK in a circadian manner; interacts with CLOCK
PMID:28985504. Phosphorylated (S122, S160, Y400, S416), SUMOylated (K195/K208/K438),
ubiquitinated (ANKRD9/proteasome).
Pharmacology. Principal target of the immunosuppressant mycophenolic acid /
mycophenolate mofetil and the antiviral ribavirin; also tiazofurin, mizoribine
[file:human/IMPDH2/IMPDH2-uniprot.txt; PMID:7763314; PMID:7903306].
Disease. Variants cause an autosomal-dominant neurodevelopmental disorder with dystonia
(IMPDH2-related dystonia / DYT; MIM:617995 in UniProt entry; Orphanet
dopa-responsive-dystonia cross-ref). The L263F polymorphism reduces activity ~10-fold
[PMID:17496727 via UniProt].

Annotation review reasoning (per-annotation notes)

Core molecular function: GO:0003938 IMP dehydrogenase activity — multiple, mutually
reinforcing lines (EXP PMID:7763314, IDA PMID:7903306, TAS PMID:1969416, IBA, IEA). All
ACCEPT; this is THE core function.
BP: de novo guanine-nucleotide synthesis. GOA has GO:0006183 (GTP biosynthetic process,
IBA + IDA), GO:0006177 (GMP biosynthetic process, IEA), GO:0006164 (purine nucleotide
biosynthetic process, IEA), GO:0097294 ('de novo' XMP biosynthetic process, IEA). The
reaction product is XMP directly; GMP/GTP synthesis follows downstream. The most precise
process term for the catalyzed step is 'de novo' XMP biosynthetic process; GMP/GTP
biosynthetic process are correct one-step-removed pathway terms. All ACCEPT (the enzyme
is genuinely the committed/rate-limiting step and is standardly annotated to the guanine
nucleotide pathway); purine nucleotide biosynthetic process is broader but correct.
Nucleotide binding (GO:0000166) / NAD binding: substrate/cosubstrate binding. NAD is a
cosubstrate. ACCEPT the IDA (PMID:14766016 reports nucleic-acid binding but the
large-scale entry has NAD/IMP binding features). Note: GO:0000166 nucleotide binding is
generic; kept as supporting, non-core.
metal ion binding (GO:0046872) / K+ binding: UniProt documents K(+) cofactor and
multiple K+ binding sites (shared between tetrameric partners). ACCEPT the IEA as
consistent with structural evidence.
catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491): correct but
uninformative parents of GO:0003938. MARK_AS_OVER_ANNOTATED (root/parent-level IEA).
Localization CC terms:
cytosol (GO:0005829): ACCEPT (IDA x2 + IEA) — core location.
cytoplasm (GO:0005737): ACCEPT (IBA/IDA/IEA) — broader but correct.
nucleus (GO:0005634): IDA PMID:14766016 (nucleic-acid binding context) + IEA. KEEP as
non-core / minor pool; genuine but secondary.
membrane (GO:0016020), peroxisomal membrane (GO:0005778), extracellular exosome
(GO:0070062), extracellular region (GO:0005576), secretory granule lumen (GO:0034774),
ficolin-1-rich granule lumen (GO:1904813): high-throughput proteomics / Reactome
neutrophil-degranulation propagation. IMPDH2 is a soluble cytosolic enzyme with no TM
segment, signal peptide, or PTS. These are contaminant / bystander / pathway-membership
localizations, not bona fide functional locations. MARK_AS_OVER_ANNOTATED (HDA/TAS,
not clearly-wrong IEA, so not REMOVE per policy).
protein binding (GO:0005515) IPIs (PMID:25416956, 32296183, 38884001, 28985504): bare
"protein binding" from large-scale Y2H / HuRI / HaloMS / interactome screens — per
curation policy, uninformative; MARK_AS_OVER_ANNOTATED (do not REMOVE experimental IPIs).
circadian rhythm (GO:0007623) IDA PMID:28985504: IMPDH2 identified as a CLOCK acetylation
substrate in a paper about circadian ureagenesis. The abstract shows IMPDH2 is a CLOCK
substrate but does not establish IMPDH2 itself functions in the circadian clock; the
process is a regulatory context. KEEP_AS_NON_CORE.
'de novo' XMP biosynthetic process (GO:0097294) IEA: most precise BP for the catalyzed
step. ACCEPT.

Deep research

Falcon deep research was NOT run for this gene (provider out of credits, HTTP 402). No
-deep-research-.md file exists. Review grounded in UniProt (P12268), the seeded GOA, and
cached publications/PMID_.md.

📄 View Raw YAML

id: P12268
gene_symbol: IMPDH2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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).
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) inference that IMPDH2 is active in the cytoplasm. Correct
      but broad; the more precise experimentally supported location is the cytosol.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0003938
    label: IMP dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) inference of IMP dehydrogenase activity, the defining
      molecular function of the IMPDH/GMPR family. This is the core function of IMPDH2.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7903306
      supporting_text: Both recombinant isoforms were
    - reference_id: PMID:1969416
      supporting_text: the rate-limiting enzyme of de novo GTP
- term:
    id: GO:0006183
    label: GTP biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1969416
      supporting_text: the rate-limiting enzyme of de novo GTP
    - reference_id: PMID:14766016
      supporting_text: IMPDH) is the rate-limiting enzyme in
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  review:
    summary: Electronic (UniRule) inference of nucleotide binding. IMPDH2 binds the
      substrate IMP and the cosubstrate NAD+, both nucleotides, at defined active-site
      residues.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: XMP biosynthesis via de novo pathway
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation of the root-level catalytic activity term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:7903306
      supporting_text: Both recombinant isoforms were
- term:
    id: GO:0003938
    label: IMP dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (ARBA/UniRule, EC 1.1.1.205, RHEA:11708) inference of IMP
      dehydrogenase activity, the core molecular function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: XMP biosynthesis via de novo pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (UniRule/SubCell SL-0191) inference of nuclear localization,
      mirroring the experimental nuclear localization reported for IMPDH.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:14766016
      supporting_text: IMPDH is found in the nucleus of human cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (UniRule/SubCell SL-0086) inference of cytoplasmic localization.
    action: ACCEPT
    reason: Correct; IMPDH2 is a soluble cytoplasmic enzyme. Redundant with the IBA and IDA
      cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (SubCell SL-0091) inference of cytosolic localization, the principal
      site of IMPDH2 catalysis.
    action: ACCEPT
    reason: Cytosol is the core, experimentally supported location (IDA in PMID:31337707 and
      HPA). This IEA is fully consistent.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0006164
    label: purine nucleotide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic annotation to purine nucleotide biosynthesis.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: XMP biosynthesis via de novo pathway
- term:
    id: GO:0006177
    label: GMP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: XMP biosynthesis via de novo pathway
    - reference_id: PMID:14766016
      supporting_text: IMPDH) is the rate-limiting enzyme in
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic annotation to the parent oxidoreductase activity term.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:7903306
      supporting_text: Xanthosine 5'-monophosphate and NADH inhibited the two isoforms
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  review:
    summary: Electronic (UniRule) inference of metal ion binding, corresponding to the
      documented monovalent cation (K+) requirement and multiple potassium binding sites.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: ligand shared between two tetrameric
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Protein binding IPI from a proteome-scale binary interactome (Y2H) screen
      (APIP, CPLANE2). Bare protein binding is uninformative about IMPDH2's function.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: a systematic map of ?14,000 high-quality human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Protein binding IPI from the HuRI all-by-all binary interactome map (multiple
      partners incl. IMPDH1, STAT3, TRAF2). Uninformative bare protein binding.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38884001
  qualifier: enables
  review:
    summary: Protein binding IPI from a HaloTag-enrichment mass-spectrometry adipocyte
      interactome screen (STAT3). Uninformative bare protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput affinity-MS interactome derived; the generic term is
      uninformative about IMPDH2 function. Kept as a valid IPI but marked over-annotated.
    supported_by:
    - reference_id: PMID:38884001
      supporting_text: map protein complex interaction networks in adipocytes
- term:
    id: GO:0097294
    label: "'de novo' XMP biosynthetic process"
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-Compara ortholog-transfer annotation to de novo XMP biosynthesis, the
      most precise process description of the reaction IMPDH2 catalyzes (IMP -> XMP).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: XMP biosynthesis via de novo pathway
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (Human Protein Atlas) localization of IMPDH2 to the
      cytosol.
    action: ACCEPT
    reason: Consistent with the primary, experimentally supported cytosolic localization of
      the enzyme and with the PMID:31337707 IDA. Core location.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0003938
    label: IMP dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:7763314
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7763314
      supporting_text: uncompetitively by mycophenolic acid with Ki values of 11 and 6 nM
    - reference_id: PMID:7763314
      supporting_text: IMPDH is an important
- term:
    id: GO:0003938
    label: IMP dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:7903306
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Quantitative kinetic characterization of the human type II enzyme; unambiguous
      experimental support for IMP dehydrogenase activity, the core molecular function.
    supported_by:
    - reference_id: PMID:7903306
      supporting_text: 9.3 microM, respectively, for IMP, and 46 and 32 microM
    - reference_id: PMID:7903306
      supporting_text: inhibited the type II enzyme with a 4.8-fold lower K than the type I
- term:
    id: GO:0006183
    label: GTP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:7903306
  qualifier: involved_in
  review:
    summary: The enzyme characterized by direct assay is the rate-limiting step feeding de
      novo guanine-nucleotide (GTP) biosynthesis.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7903306
      supporting_text: Xanthosine 5'-monophosphate and NADH inhibited the two isoforms
    - reference_id: PMID:1969416
      supporting_text: the rate-limiting enzyme of de novo GTP
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:31337707
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Experimental cytosolic localization; core location of the enzyme. Also documents
      the regulated macro-assembly (filament) behavior of IMPDH2.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
    - reference_id: PMID:31337707
      supporting_text: assembles with IMPDH2 into rodlike filaments
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28985504
  qualifier: enables
  review:
    summary: IPI recording the IMPDH2-CLOCK interaction (IMPDH2 is a CLOCK acetylation
      substrate). Bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:28985504
      supporting_text: as acetylation substrates of CLOCK
- term:
    id: GO:0007623
    label: circadian rhythm
  evidence_type: IDA
  original_reference_id: PMID:28985504
  qualifier: involved_in
  review:
    summary: IMPDH2 was identified as an acetylation substrate of the circadian
      acetyltransferase CLOCK, alongside NDUFA9, in a study of circadian ureagenesis.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:28985504
      supporting_text: as acetylation substrates of CLOCK
    - reference_id: PMID:28985504
      supporting_text: acting as a rhythmic acetyl-transferase for metabolic
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: Reactome pathway-membership annotation placing IMPDH2 in exocytosis of secretory
      granule lumen proteins (neutrophil degranulation), yielding an extracellular-region
      location.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: the first committed and rate-limiting
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome pathway-membership annotation (exocytosis of ficolin-rich granule
      lumen proteins) placing IMPDH2 in the extracellular region.
    action: MARK_AS_OVER_ANNOTATED
    reason: As above, this derives from neutrophil-degranulation granule proteomics and does
      not represent a genuine secreted/extracellular function for this cytosolic enzyme.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: the first committed and rate-limiting
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation pathway-membership annotation to secretory
      granule lumen.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: the first committed and rate-limiting
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation pathway-membership annotation to ficolin-1-rich
      granule lumen.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same neutrophil-granule proteomics origin; a bystander localization rather than a
      functional site for the cytosolic IMPDH2 enzyme.
    supported_by:
    - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
      supporting_text: the first committed and rate-limiting
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane-proteome (NK-cell) mass-spectrometry detection of
      IMPDH2, yielding a generic membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: transiently associated with membranes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of IMPDH2 in B-cell exosomes.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: identified 539 proteins, including known and not
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-73794
  qualifier: located_in
  review:
    summary: Reactome annotation for the IMP + H2O + NAD+ to XMP + NADH + H+ reaction placing
      the IMPDH1,2 activity in the cytosol.
    action: ACCEPT
    reason: Correct cytosolic localization tied directly to the catalyzed reaction; fully
      consistent with the core function and location.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9678749
  qualifier: located_in
  review:
    summary: Reactome annotation (IMPDH tetramers bind IMPDH inhibitors) placing IMPDH2 in
      the cytosol.
    action: ACCEPT
    reason: Correct cytosolic localization; also reflects the tetrameric assembly and
      inhibitor (e.g. mycophenolic acid) binding that are hallmark features of the enzyme.
    supported_by:
    - reference_id: PMID:7763314
      supporting_text: uncompetitively by mycophenolic acid with Ki values of 11 and 6 nM
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9748945
  qualifier: located_in
  review:
    summary: Reactome annotation (IMPDH tetramers dehydrogenate 6TIMP to 6TXMP, thiopurine
      metabolism) placing IMPDH2 in the cytosol.
    action: ACCEPT
    reason: Correct cytosolic localization; captures the enzyme's ability to also
      dehydrogenate the thiopurine analog 6-thio-IMP, consistent with its IMP dehydrogenase
      activity.
    supported_by:
    - reference_id: PMID:31337707
      supporting_text: Under basal conditions ANKRD9 is largely segregated from the cytosolic
        IMPDH2
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: HDA
  original_reference_id: PMID:21525035
  qualifier: located_in
  review:
    summary: High-throughput detection of IMPDH2 among proteins co-purifying with PEX14
      complexes from peroxisomal membranes.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21525035
      supporting_text: isolating native peroxisomal membrane
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:14766016
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:14766016
      supporting_text: IMPDH is found in the nucleus of human cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:14766016
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization of IMPDH.
    action: ACCEPT
    reason: Consistent with the soluble cytoplasmic/cytosolic nature of the enzyme; supports
      the core location alongside the cytosol annotations.
    supported_by:
    - reference_id: PMID:14766016
      supporting_text: IMPDH is found in the nucleus of human cells
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IDA
  original_reference_id: PMID:14766016
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:14766016
      supporting_text: bind single-stranded nucleic acids with nanomolar affinity via the
- term:
    id: GO:0003938
    label: IMP dehydrogenase activity
  evidence_type: TAS
  original_reference_id: PMID:1969416
  qualifier: enables
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1969416
      supporting_text: the rate-limiting enzyme of de novo GTP
core_functions:
- description: NAD+-dependent oxidation of IMP to XMP, the committed and rate-limiting step
    of de novo guanine-nucleotide biosynthesis, performed by the cytosolic IMPDH2 homotetramer.
  molecular_function:
    id: GO:0003938
    label: IMP dehydrogenase activity
  directly_involved_in:
  - id: GO:0006177
    label: GMP biosynthetic process
  - id: GO:0006164
    label: purine nucleotide biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:7903306
    supporting_text: 9.3 microM, respectively, for IMP, and 46 and 32 microM
  - reference_id: PMID:1969416
    supporting_text: the rate-limiting enzyme of de novo GTP
  - reference_id: file:human/IMPDH2/IMPDH2-uniprot.txt
    supporting_text: XMP biosynthesis via de novo pathway
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- description: Structure-guided separation-of-function mutants that abolish CBS-subdomain
    nucleic-acid binding while preserving catalysis, to test the moonlighting nuclear role.
- description: 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.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
    using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14766016
  title: Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes the rate-limiting role, the CBS-subdomain
      single-stranded nucleic-acid-binding moonlighting activity, and nuclear localization.
- id: PMID:1969416
  title: Two distinct cDNAs for human IMP dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; defines the two human isoforms (type I=IMPDH1, type
      II=IMPDH2) and the rate-limiting role in de novo GTP biosynthesis.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput membrane proteome; supports only a peripheral/contaminant
      membrane detection of the cytosolic enzyme.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications
    for exosome biogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; IMPDH2 detected as an abundant cytosolic protein, not
      a functional exosomal component.
- id: PMID:21525035
  title: PEX14 is required for microtubule-based peroxisome motility in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PEX14 complex proteomics; IMPDH2 is a co-purifying abundant cytosolic
      protein, not a genuine peroxisomal-membrane resident.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale binary interactome; source of uninformative protein binding
      IPIs.
- id: PMID:28985504
  title: CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; identifies IMPDH2 as a CLOCK acetylation substrate and
      interactor (circadian post-translational regulation), a non-core regulatory context.
- id: PMID:31337707
  title: ANKRD9 is a metabolically-controlled regulator of IMPDH2 abundance and macro-assembly.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes cytosolic localization, the rate-limiting role
      in GTP biosynthesis, ANKRD9-mediated degradation, and regulated filament (rod) assembly.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI all-by-all interactome; source of uninformative protein binding IPIs.
- id: PMID:38884001
  title: Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HaloTag affinity-MS adipocyte interactome; source of an uninformative
      protein binding IPI.
- id: PMID:7763314
  title: Recombinant human inosine monophosphate dehydrogenase type I and type II proteins.
    Purification and characterization of inhibitor binding.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; experimental characterization of purified human type II
      (IMPDH2) enzyme and mycophenolic acid / mizoribine-monophosphate inhibitor binding.
- id: PMID:7903306
  title: Characterization of human type I and type II IMP dehydrogenases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; quantitative kinetics of purified human type II enzyme
      (Km, kcat, tetramer, product inhibition), the primary support for the core function.
- id: Reactome:R-HSA-6798748
  title: Exocytosis of secretory granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-73794
  title: IMP + H2O + NAD+ => XMP + NADH + H+ [IMPDH1,2]
  findings: []
- id: Reactome:R-HSA-9678749
  title: IMPDH tetramers bind IMPDH inhibitors
  findings: []
- id: Reactome:R-HSA-9748945
  title: IMPDH tetramers dehydrogenate 6TIMP to 6TXMP
  findings: []
- id: file:human/IMPDH2/IMPDH2-uniprot.txt
  title: UniProtKB entry P12268 (IMPDH2_HUMAN)
  findings: []

IMPDH2

Gene Description