IMD4 (YML056C) encodes one of three functional inosine-5'-monophosphate dehydrogenases (IMPDH; with IMD2 and IMD3; IMD1 is a pseudogene) of Saccharomyces cerevisiae. The enzyme catalyses the NAD+-dependent oxidation of IMP to xanthosine 5'-monophosphate (XMP), the first committed and rate-limiting step of guanine nucleotide synthesis from IMP; XMP is then aminated to GMP by Gua1. Deletion of all four IMD genes causes guanine auxotrophy, and IMD4 alone is sufficient for guanine prototrophy, but unlike the transcriptionally inducible IMD2, IMD4 cannot confer resistance to mycophenolic acid (MPA) and its product is efficiently trapped as the MPA-inhibited covalent intermediate in vivo. Imd4 contains a CBS (Bateman) regulatory domain and assembles with Imd2 and Imd3 into mixed IMPDH tetramers. It is a cytoplasmic enzyme; it has also been recovered among proteins cross-linked to mRNA in a proteome-wide survey.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000166 nucleotide binding | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: UniRule (HAMAP MF_03156) IMPDH rule assigns generic nucleotide binding (IMP/NAD+ substrate binding). Implied by the catalytic activity and uninformative on its own. Reason: True (binds IMP, XMP, NAD+) but subsumed by IMP dehydrogenase activity. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, |
| GO:0003729 mRNA binding | HDA PMID:23222640 Global analysis of yeast mRNPs. | KEEP AS NON CORE | Summary: Mitchell et al. (2013) global mRNA-protein cross-linking (HDA) recovered Imd4 among 120 mRNA-binding proteins including metabolic enzymes. Nucleic-acid binding by IMPDH CBS domains is described for other species, but for Imd4 this is a single high-throughput hit with no defined target or function. Reason: High-throughput observation of unknown functional relevance; not part of the catalytic role. Supporting Evidence: PMID:23222640 These include kinases, RNA-modification enzymes, metabolic enzymes and tRNA- and rRNA-metabolism factors. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IMPDH/GMPR family mapping to the root "catalytic activity" term; correct but uninformative. Reason: Replace with the specific activity. Proposed replacements: IMP dehydrogenase activity Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, |
| GO:0003938 IMP dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER node PTN000226903 (eukaryotic and bacterial IMPDHs incl. E. coli GuaB, human IMPDH2, S. pombe gua1). Imd4 retains all catalytic features and supports guanine prototrophy on its own; correct. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro IPR005990 IMPDH, RHEA:11708, EC 1.1.1.205, HAMAP UniRule); correct. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways DENOVOPURINE2-PWY (superpathway of purine nucleotides de novo biosynthesis II) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways DENOVOPURINE3-PWY (de novo biosynthesis of purine nucleotides) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PRPP-PWY-1 (superpathway of histidine, purine and pyrimidine biosynthesis) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PWY-6125 (superpathway of guanosine nucleotides de novo biosynthesis II) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PWY-7221 (guanosine ribonucleotides de novo biosynthesis) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0003938 IMP dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PWY3O-285 (superpathway of purine biosynthesis and salvage pathways) assigns IMD2, IMD3 and IMD4 to IMP-DEHYDROG-RXN (EC 1.1.1.205, cited PMID:12746440); correct for Imd4, which alone supports guanine prototrophy. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, PMID:12746440 Although neither IMD3 nor IMD4 could confer drug resistance to cells lacking IMD2, either alone was sufficient to confer guanine prototrophy. |
| GO:0005515 protein binding | IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine... | REMOVE | Summary: Gavin et al. 2006 TAP-MS: Imd4 co-purifies/interacts with its paralog Imd3 (P50095). This reflects assembly of mixed IMPDH heterotetramers (McPhillips et al. 2004), a structural feature of the enzyme rather than a distinct molecular function; "protein binding" adds no information. Reason: Uninformative protein binding; the Imd3-Imd4 association is real (heteromeric IMPDH tetramers) but is captured by the IMPDH activity/complex, not by this term. Removal does not mean the interaction is false. Supporting Evidence: PMID:15292516 Purification of the tagged IMD gene products reveals that the family of polypeptides coassemble to form heteromeric IMPDH complexes, suggesting that they form mixed tetramers. |
| GO:0005515 protein binding | IPI PMID:18467557 An in vivo map of the yeast protein interactome. | REMOVE | Summary: Tarassov et al. 2008 DHFR-PCA: Imd4 co-purifies/interacts with its paralog Imd3 (P50095). This reflects assembly of mixed IMPDH heterotetramers (McPhillips et al. 2004), a structural feature of the enzyme rather than a distinct molecular function; "protein binding" adds no information. Reason: Uninformative protein binding; the Imd3-Imd4 association is real (heteromeric IMPDH tetramers) but is captured by the IMPDH activity/complex, not by this term. Removal does not mean the interaction is false. Supporting Evidence: PMID:15292516 Purification of the tagged IMD gene products reveals that the family of polypeptides coassemble to form heteromeric IMPDH complexes, suggesting that they form mixed tetramers. |
| GO:0005515 protein binding | IPI PMID:18719252 High-quality binary protein interaction map of the yeast int... | REMOVE | Summary: Yu et al. 2008 binary Y2H map: Imd4 co-purifies/interacts with its paralog Imd3 (P50095). This reflects assembly of mixed IMPDH heterotetramers (McPhillips et al. 2004), a structural feature of the enzyme rather than a distinct molecular function; "protein binding" adds no information. Reason: Uninformative protein binding; the Imd3-Imd4 association is real (heteromeric IMPDH tetramers) but is captured by the IMPDH activity/complex, not by this term. Removal does not mean the interaction is false. Supporting Evidence: PMID:15292516 Purification of the tagged IMD gene products reveals that the family of polypeptides coassemble to form heteromeric IMPDH complexes, suggesting that they form mixed tetramers. |
| GO:0005515 protein binding | IPI PMID:31454312 The role of structural pleiotropy and regulatory evolution i... | REMOVE | Summary: Marchant et al. 2019 paralog heteromer PCA study: Imd4 co-purifies/interacts with its paralog Imd3 (P50095). This reflects assembly of mixed IMPDH heterotetramers (McPhillips et al. 2004), a structural feature of the enzyme rather than a distinct molecular function; "protein binding" adds no information. Reason: Uninformative protein binding; the Imd3-Imd4 association is real (heteromeric IMPDH tetramers) but is captured by the IMPDH activity/complex, not by this term. Removal does not mean the interaction is false. Supporting Evidence: PMID:15292516 Purification of the tagged IMD gene products reveals that the family of polypeptides coassemble to form heteromeric IMPDH complexes, suggesting that they form mixed tetramers. |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | REMOVE | Summary: Michaelis et al. 2023 interactome: Imd4 co-purifies/interacts with its paralog Imd3 (P50095). This reflects assembly of mixed IMPDH heterotetramers (McPhillips et al. 2004), a structural feature of the enzyme rather than a distinct molecular function; "protein binding" adds no information. Reason: Uninformative protein binding; the Imd3-Imd4 association is real (heteromeric IMPDH tetramers) but is captured by the IMPDH activity/complex, not by this term. Removal does not mean the interaction is false. Supporting Evidence: PMID:15292516 Purification of the tagged IMD gene products reveals that the family of polypeptides coassemble to form heteromeric IMPDH complexes, suggesting that they form mixed tetramers. |
| GO:0005737 cytoplasm | HDA PMID:14562095 Global analysis of protein localization in budding yeast. | ACCEPT | Summary: Huh et al. 2003 GFP localisation: Imd4-GFP cytoplasmic; correct for IMPDH. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA is_active_in cytoplasm (PTN000226902; donors include Imd2/Imd3/Imd4 and human IMPDH); consistent with experimental data. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005737 cytoplasm | IDA PMID:23222640 Global analysis of yeast mRNPs. | ACCEPT | Summary: Mitchell et al. (2013) localised the newly identified mRNA-binding proteins, including Imd4, in unstressed and stressed cells; cytoplasmic localisation agrees with other data. Supporting Evidence: PMID:23222640 These proteins show dynamic subcellular localization during stress, including assembly into stress granules and processing bodies (P bodies). |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: HAMAP UniRule/SubCell mapping to cytoplasm; correct. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways DENOVOPURINE2-PWY; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways DENOVOPURINE3-PWY; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways PRPP-PWY-1; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways PWY-6125; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways PWY-7221; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Default cytosol compartment from YeastPathways PWY3O-285; consistent with the HAMAP/HDA/IDA cytoplasmic localisation of IMPDH (no organellar targeting signal). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156, |
| GO:0006164 purine nucleotide biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro IPR005990 (IMPDH) mapping to purine nucleotide biosynthesis; correct parent of GMP biosynthesis. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore |
| GO:0006164 purine nucleotide biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways DENOVOPURINE2-PWY RCA: IMPDH is a step of purine nucleotide synthesis; correct though general (GMP biosynthesis is the specific process). Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore PMID:12746440 The simultaneous deletion of all four IMD genes was lethal unless growth media were supplemented with guanine. |
| GO:0006164 purine nucleotide biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways DENOVOPURINE3-PWY RCA: correct though general. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore PMID:12746440 The simultaneous deletion of all four IMD genes was lethal unless growth media were supplemented with guanine. |
| GO:0006177 GMP biosynthetic process | IEA GO_REF:0000104 | ACCEPT | Summary: HAMAP UniRule mapping to GMP biosynthetic process; IMP to XMP is the first committed step of GMP synthesis. Correct and the best process term. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore PMID:12746440 The simultaneous deletion of all four IMD genes was lethal unless growth media were supplemented with guanine. |
| GO:0006183 GTP biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN000226903, donors human IMPDH2 and S. pombe gua1) for GTP biosynthesis; IMPDH is rate-limiting for the guanine nucleotide (GTP) pool. Acceptable. Supporting Evidence: PMID:12746440 IMP dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo synthesis of GTP. |
| GO:0009165 nucleotide biosynthetic process | RCA GO_REF:0000123 | MODIFY | Summary: Superpathway inflation: YeastPathways PRPP-PWY-1 (histidine, purine and pyrimidine biosynthesis) yields the very broad "nucleotide biosynthetic process" for IMPDH. Imd4 functions specifically in GMP synthesis. Reason: Too general; use GMP biosynthetic process. Proposed replacements: GMP biosynthetic process Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR015875 (IMPDH/GMPR conserved site) mapping to oxidoreductase activity; correct but too general. Reason: Replace with the specific activity. Proposed replacements: IMP dehydrogenase activity Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Reaction=IMP + NAD(+) + H2O = XMP + NADH + H(+); Xref=Rhea:RHEA:11708, |
| GO:0043101 purine-containing compound salvage | RCA GO_REF:0000123 | MARK AS OVER ANNOTATED | Summary: Superpathway inflation from YeastPathways PWY3O-285 (purine biosynthesis and salvage). IMPDH converts IMP to XMP whatever the source of IMP; it does not salvage a purine base or nucleoside. The salvage enzymes for guanylate are Hpt1 and Xpt1. Reason: IMPDH is an interconversion step downstream of both de novo and salvage IMP supply, not a salvage reaction. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore |
| GO:0046872 metal ion binding | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: HAMAP UniRule metal ion binding (monovalent K+ activation site of IMPDH); plausible by homology but uninformative. Reason: Cofactor (K+) binding inferred from family; not a distinct function. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt Name=K(+); Xref=ChEBI:CHEBI:29103; Evidence={ECO:0000255|HAMAP- |
| GO:0106387 'de novo' GMP biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PWY-6125 RCA: 'de novo' GMP biosynthetic process (GMP formation through an IMP intermediate); IMPDH catalyses the first step. Correct. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore PMID:12746440 The simultaneous deletion of all four IMD genes was lethal unless growth media were supplemented with guanine. |
| GO:0106387 'de novo' GMP biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways PWY-7221 RCA: 'de novo' GMP biosynthetic process; correct. Supporting Evidence: file:yeast/IMD4/IMD4-uniprot.txt step in the de novo synthesis of guanine nucleotides, and therefore PMID:12746440 The simultaneous deletion of all four IMD genes was lethal unless growth media were supplemented with guanine. |
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Download this section (compressed HTML)Q: What is the subunit composition of IMPDH tetramers in unstressed versus MPA- or guanine-limited cells, and does Imd4 incorporation change catalytic or drug-sensitivity properties of Imd2-containing heterotetramers?
Experiment: Purify homotetrameric Imd4 and defined Imd2/Imd4 heterotetramers and measure kcat/Km for IMP and NAD+, MPA IC50 and GTP/ATP allosteric effects through the CBS domain.
Inosine monophosphate dehydrogenase; catalyzes the rate-limiting step in the de novo synthesis of GTP; member of a four-gene family in S. cerevisiae, constitutively expressed; IMD4 has a paralog, IMD3, that arose from the whole genome duplication
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