Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1; EC 1.1.1.205) catalyses 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 of de novo guanine-nucleotide (GMP) biosynthesis; XMP is subsequently aminated to GMP by GMP synthase (GMPS). The enzyme is a cytosolic homotetramer built from a catalytic (beta/alpha)8 TIM-barrel domain plus a regulatory subdomain of two tandem CBS (Bateman) domains, uses a monovalent cation (K+) cofactor, and can assemble into higher-order filaments ("rods and rings"/cytoophidia). IMPDH1 is broadly expressed but strongly enriched in retinal photoreceptors; a reported single-stranded nucleic-acid-binding activity mediated by the CBS subdomain suggests an additional, less well-defined role in nucleic-acid metabolism. Because guanine-nucleotide supply is coupled to cell proliferation, IMPDH is a validated target of immunosuppressive (mycophenolic acid, mizoribine), antiviral (ribavirin) and antitumour drugs. Dominant IMPDH1 mutations, many clustered in the CBS subdomain, cause retinitis pigmentosa 10 (RP10) and Leber congenital amaurosis (LCA11), degenerative diseases of the retina.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytoplasmic localization. IMPDH1 is a soluble cytosolic enzyme, consistent with its role in the cytosolic de novo purine pathway. Reason: IBA is_active_in cytoplasm is correct and consistent with the UniProt subcellular location and with the more specific IDA cytosol annotation. This is a core localization for the enzyme's catalytic activity. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003938 IMP dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IMP dehydrogenase activity (EC 1.1.1.205) is the defining, experimentally and phylogenetically well-supported molecular function of IMPDH1: NAD+-dependent oxidation of IMP to XMP. Reason: This is the core molecular function. Supported by the enzyme name, EC number, catalytic-activity reaction in UniProt, and by direct biochemical characterization of human type I IMPDH; the IBA is at the correct level of specificity. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+) PMID:1969416 IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP |
| GO:0006183 GTP biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IMPDH1 contributes to GTP biosynthesis only indirectly: it makes XMP (->GMP), and GMP is subsequently phosphorylated (GMP->GDP->GTP) by other enzymes. Reason: The direct committed step catalysed by IMPDH1 produces XMP en route to GMP, not GTP. GTP biosynthesis is several enzymatic steps downstream, so this term overstates the enzyme's direct role. It is biologically defensible as a broader pathway contribution but is not the core function; the more precise BP terms are XMP/GMP biosynthetic process. Supporting Evidence: PMID:1969416 IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP |
| GO:0000166 nucleotide binding | IEA GO_REF:0000104 | MODIFY | Summary: IMPDH1 binds the nucleotide cofactor NAD+ and the nucleotide substrate IMP; a generic "nucleotide binding" annotation captures this but at a very shallow level. Reason: The term is not wrong but is uninformative given that the specific ligands (NAD+, IMP) and the catalytic activity are known. Replace with the specific cofactor-binding molecular function NAD binding (GO:0051287); the catalytic activity term already covers IMP as substrate. Proposed replacements: NAD binding Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+) |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Root-level catalytic activity term derived from an InterPro domain mapping. IMPDH1 is an enzyme, so this is true but maximally uninformative. Reason: "catalytic activity" is the top of the MF catalytic branch and adds nothing beyond the specific, well-established IMP dehydrogenase activity. Replace with GO:0003938 (IMP dehydrogenase activity). Proposed replacements: IMP dehydrogenase activity Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+) |
| GO:0003938 IMP dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule/RHEA/EC-based) assertion of the core IMP dehydrogenase activity, duplicating the IBA and TAS annotations of the same term. Reason: Correct and specific core molecular function; the IEA mapping from EC 1.1.1.205 / RHEA:11708 is well grounded. Duplicate of GO:0003938 by other evidence codes, which is acceptable. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+) |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear localization transferred electronically, ultimately reflecting the reported nuclear pool of IMPDH linked to its nucleic-acid-binding activity. Reason: IMPDH is detected in the nucleus (PMID:14766016), but the enzyme's core catalytic role in de novo GMP synthesis operates in the cytosol. Nuclear localization relates to the moonlighting single-stranded nucleic-acid-binding activity and is a non-core feature. Supporting Evidence: PMID:14766016 IMPDH is found in the nucleus of human cells, as |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic cytoplasmic localization, consistent with the enzyme's soluble cytosolic distribution. Reason: Correct core localization; duplicates the IBA/IDA cytoplasm and IDA cytosol annotations. The cytosol is where IMPDH1 performs its catalytic function. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006164 purine nucleotide biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: Broad "purine nucleotide biosynthetic process" from an InterPro mapping. IMPDH1 does act in de novo purine (guanine) nucleotide biosynthesis, but this is a high-level parent term. Reason: Correct branch but too general; the specific, well-defined role is in guanosine (GMP)/XMP biosynthesis. Replace with the more precise GMP biosynthetic process (GO:0006177), which is the committed step catalysed by IMPDH1. Proposed replacements: GMP biosynthetic process Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt step in the de novo synthesis of guanine nucleotides |
| GO:0006177 GMP biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: GMP biosynthetic process, the pathway in which IMPDH1 catalyses the committed, rate-limiting step (IMP -> XMP -> GMP). Reason: This is the correct, appropriately specific core biological process for IMPDH1. The enzyme makes XMP, the immediate committed precursor of GMP, in the de novo guanine-nucleotide pathway. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt step in the de novo synthesis of guanine nucleotides |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Parent oxidoreductase activity from an InterPro mapping. IMPDH1 is an NAD+-dependent oxidoreductase, but this is a broad ancestor of its specific activity. Reason: True but too general; the specific dehydrogenase activity is IMP dehydrogenase activity (GO:0003938), a descendant of oxidoreductase activity. Replace with the specific term. Proposed replacements: IMP dehydrogenase activity Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+) |
| GO:0046872 metal ion binding | IEA GO_REF:0000104 | MODIFY | Summary: Metal-ion binding assigned by UniRule. IMPDH1 requires a monovalent cation (K+) cofactor, with several structurally defined K+ binding sites at the tetramer interface. Reason: The generic "metal ion binding" understates the specific, functionally important requirement for a monovalent cation (potassium). Replace with potassium ion binding (GO:0030955), which the UniProt COFACTOR and K+ BINDING site annotations support. Proposed replacements: potassium ion binding Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt Name=K(+) |
| GO:0097294 'de novo' XMP biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: 'de novo' XMP biosynthetic process is the most precise biological process for the reaction IMPDH1 actually catalyses: IMP -> XMP is the single committed step of de novo XMP synthesis. Reason: Directly matches the UniProt pathway annotation ("XMP biosynthesis via de novo pathway; XMP from IMP: step 1/1") and the catalytic reaction. This is arguably the single most accurate BP term for IMPDH1 and a core process. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt XMP biosynthesis via de novo pathway |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localization (HPA) to the cytosol, the compartment where IMPDH1 carries out de novo GMP synthesis. Reason: Experimental (IDA) cytosolic localization is the most specific and accurate core location, consistent with the soluble cytosolic purine pathway and the broader cytoplasm annotations. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Extracellular localization inferred from a Reactome neutrophil-degranulation exocytosis event (secretory granule proteins), not from a dedicated function of IMPDH1. Reason: IMPDH1 is a soluble cytosolic enzyme. Its appearance in the extracellular region derives from bulk proteomic detection of the neutrophil granule/secretome and does not reflect a genuine secreted function. This is a bystander over-annotation, not a core localization. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | Summary: Duplicate extracellular-region localization from a Reactome azurophil-granule exocytosis event. Reason: Same rationale as the other extracellular-region Reactome annotations: IMPDH1 is cytosolic, and its granule-lumen/extracellular assignment reflects neutrophil-degranulation proteomics rather than a genuine secreted role. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Duplicate extracellular-region localization from a Reactome ficolin-rich granule exocytosis event. Reason: As with the other Reactome degranulation-derived localizations, this reflects bulk granule/secretome proteomics rather than a genuine extracellular function of the cytosolic enzyme IMPDH1. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | MARK AS OVER ANNOTATED | Summary: Secretory granule lumen localization from the Reactome neutrophil-degranulation pathway. Reason: Cytosolic IMPDH1 is detected in neutrophil granule proteomes, but this is a bystander/contaminant-type localization from degranulation datasets rather than a genuine granule-lumen residence relevant to its enzymatic function. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | Summary: Azurophil granule lumen localization from the Reactome neutrophil-degranulation pathway. Reason: As above: derives from neutrophil granule proteomics of the cytosolic enzyme IMPDH1 and does not reflect a core, functionally meaningful granule-lumen localization. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | MARK AS OVER ANNOTATED | Summary: Ficolin-1-rich granule lumen localization from the Reactome neutrophil-degranulation pathway. Reason: Same bystander-proteomics rationale: cytosolic IMPDH1 appearing in a granule lumen dataset does not constitute a genuine, core subcellular location for the enzyme. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73794 | ACCEPT | Summary: Cytosolic localization asserted by the Reactome IMP -> XMP reaction, the core catalytic event of IMPDH1. Reason: Correct core localization tied directly to the catalytic reaction; consistent with the IDA cytosol and cytoplasm annotations. Supporting Evidence: Reactome:R-HSA-73794 IMP dehydrogenase 1 and 2 (IMPDH1,2) catalyze the irreversible dehydrogenation of inosine 5'-monophosphate (IMP) to form xanthosine 5'-monophosphate (XMP) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9678749 | ACCEPT | Summary: Cytosolic localization from the Reactome "IMPDH tetramers bind IMPDH inhibitors" reaction (drug-binding context). Reason: The cytosol is the correct core compartment for IMPDH1; the annotation arises from a drug/inhibitor-binding reaction but the localization itself is accurate and duplicates the other cytosol annotations. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9748945 | ACCEPT | Summary: Cytosolic localization from the Reactome "IMPDH tetramers dehydrogenate 6TIMP to 6TXMP" reaction (thiopurine metabolism context). Reason: Correct core localization. The reaction reflects IMPDH turnover of a thiopurine metabolite, but the cytosolic assignment is accurate and duplicates the other cytosol annotations. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003676 nucleic acid binding | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | KEEP AS NON CORE | Summary: Direct demonstration that IMPDH (both human isoforms) binds single-stranded nucleic acids with nanomolar affinity via its CBS subdomain, with ~100 nucleotides bound per tetramer. Reason: This is a genuine, experimentally supported moonlighting activity of IMPDH1 mediated by the regulatory CBS (Bateman) subdomain, and several RP10/LCA disease variants alter this nucleic-acid affinity. However, the enzyme's core function is IMP dehydrogenase catalysis; the nucleic-acid-binding role is regulatory/moonlighting and best retained as non-core. Supporting Evidence: PMID:14766016 bind single-stranded nucleic acids with nanomolar affinity via the |
| GO:0003677 DNA binding | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | KEEP AS NON CORE | Summary: IMPDH was shown by immunoprecipitation to bind DNA (and RNA) in vivo, an extension of its single-stranded nucleic-acid-binding activity. Reason: Experimentally supported (IDA) but represents the moonlighting nucleic-acid interaction rather than a sequence-specific transcription-factor-type DNA binding. It is a non-core, regulatory activity distinct from the enzyme's committed metabolic role; retained as non-core per curation policy for experimental annotations. Supporting Evidence: PMID:14766016 immunoprecipitation experiments show that IMPDH binds both RNA and DNA in vivo |
| GO:0005634 nucleus | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | KEEP AS NON CORE | Summary: Direct detection of IMPDH in the nucleus of human cells, consistent with its nucleic-acid-binding activity. Reason: Experimentally supported nuclear pool, but the enzyme's core catalytic function in de novo GMP synthesis is cytosolic. Nuclear localization is tied to the moonlighting nucleic-acid-binding role and is non-core. Supporting Evidence: PMID:14766016 IMPDH is found in the nucleus of human cells, as |
| GO:0005737 cytoplasm | IDA PMID:14766016 Inosine 5'-monophosphate dehydrogenase binds nucleic acids i... | ACCEPT | Summary: Direct localization of IMPDH to the cytoplasm, its principal compartment. Reason: Experimental (IDA) cytoplasmic localization corroborates the core cytosolic residence where IMPDH1 catalyses IMP -> XMP; consistent with the IDA cytosol and IBA/IEA cytoplasm annotations. Supporting Evidence: file:human/IMPDH1/IMPDH1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003938 IMP dehydrogenase activity | TAS PMID:1969416 Two distinct cDNAs for human IMP dehydrogenase. | ACCEPT | Summary: Traceable author statement (original cloning paper) that the two human IMPDH cDNAs encode IMP dehydrogenase, the rate-limiting enzyme of de novo guanine nucleotide synthesis. Reason: Core molecular function supported by the foundational cloning/characterization paper for human IMPDH1 (type I). Duplicates GO:0003938 by other evidence codes, which is acceptable. Supporting Evidence: PMID:1969416 IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP |
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Download this section (compressed HTML)Q: Is the single-stranded nucleic-acid-binding activity of the CBS subdomain a physiologically regulated function of IMPDH1 in photoreceptors, and does its disruption (as by RP10/LCA CBS-domain variants) cause disease independently of catalytic activity?
Q: What is the functional significance of IMPDH1 filament ("rods and rings"/ cytoophidia) assembly for guanine-nucleotide homeostasis in the retina?
Experiment: Separate-of-function IMPDH1 alleles that abolish catalysis while preserving nucleic-acid binding (and vice versa) expressed in photoreceptor models, to test whether RP10/LCA phenotypes arise from loss of catalysis, loss/alteration of nucleic-acid binding, or a dominant-negative filament defect.
Experiment: Cryo-EM and cellular imaging of retina-specific IMPDH1 isoforms to determine how the extended N-terminal retinal isoforms modulate filament assembly and GTP/GDP-dependent allosteric regulation.
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