Regulatory subunit (Idh1p, YNL037C) of the mitochondrial NAD+-dependent isocitrate dehydrogenase (NAD-IDH, EC 1.1.1.41), a hetero-octamer of four Idh1 and four Idh2 subunits organised as Idh1/Idh2 heterodimers. The enzyme oxidatively decarboxylates isocitrate to 2-oxoglutarate with NAD+ in the mitochondrial matrix and is a rate-limiting step of the TCA cycle. Idh2 carries the catalytic site, whereas the homologous Idh1 site binds isocitrate and AMP and confers cooperativity and allosteric activation by AMP; Idh1 residues also contribute to the Idh2 active site. Loss of either subunit abolishes NAD-IDH activity, impairs growth on acetate and glycerol and increases petite formation. Idh1 has also been reported to bind the 5'-untranslated leaders of mitochondrial mRNAs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA from InterPro IPR019818 (IDH/IMDH conserved site). IDH1 is the regulatory subunit but its residues (Lys-183, Asp-217) contribute to the IDH2 catalytic site, and its regulatory site is homologous to the catalytic site; metal binding at the subunit interfaces is plausible but is a cofactor property, not IDH1's core role. Supporting Evidence: file:yeast/IDH1/IDH1-uniprot.txt Note=Binds 1 Mg(2+) or Mn(2+) ion per subunit. PMID:11042198 the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other |
| GO:0004449 isocitrate dehydrogenase (NAD+) activity | IDA PMID:16884682 Novel allosteric properties produced by residue substitution... | ACCEPT | Summary: IDA (contributes_to) from Hu & McAlister-Henn 2006 on the purified hetero-octamer. IDH1 is the regulatory subunit (AMP activation, isocitrate cooperativity) and contributes residues to the IDH2 catalytic site, so contributes_to is the right qualifier. Supporting Evidence: PMID:16884682 Yeast NAD+-specific isocitrate dehydrogenase (IDH) is an octamer of four IDH1 and four IDH2 subunits, and the basic structural unit of the enzyme is an IDH1/IDH2 heterodimer PMID:11042198 IDH2 was previously shown to contain the catalytic site, whereas IDH1 contributes regulatory properties including cooperativity with respect to isocitrate and allosteric activation by AMP |
| GO:0004449 isocitrate dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: IEA from Rhea/EC 1.1.1.41 mapping asserts 'enables' isocitrate dehydrogenase (NAD+) activity. IDH1 is the non-catalytic regulatory subunit: replacement of all four divergent residues in the IDH1 site only reduces Vmax 17-fold versus 30->300-fold for IDH2, and IDH1 is required for AMP activation. The activity is correctly captured with contributes_to (IDA/RCA rows); 'enables' over-states IDH1's role. Supporting Evidence: PMID:11714283 Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP PMID:11042198 IDH2 was previously shown to contain the catalytic site, whereas IDH1 contributes regulatory properties including cooperativity with respect to isocitrate and allosteric activation by AMP |
| GO:0004449 isocitrate dehydrogenase (NAD+) activity | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways TCA-EUK-PWY with contributes_to qualifier. Appropriate for the regulatory subunit of the hetero-octameric NAD-IDH. Supporting Evidence: PMID:11042198 IDH2 was previously shown to contain the catalytic site, whereas IDH1 contributes regulatory properties including cooperativity with respect to isocitrate and allosteric activation by AMP file:yeast/IDH1/IDH1-uniprot.txt Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH; |
| GO:0005515 protein binding | IPI PMID:11042198 Subunit interactions of yeast NAD+-specific isocitrate dehyd... | REMOVE | Summary: IPI IDH1-IDH2 interaction (two-hybrid and mutational analysis). The interaction is real and obligate (IDH1 and IDH2 form the heterodimeric unit of the hetero-octamer); removal does not mean it is false, only that 'protein binding' carries no functional information. It is captured by part_of isocitrate dehydrogenase complex (NAD+) (GO:0045242). Supporting Evidence: PMID:11042198 interactions between IDH1 and IDH2 were detected using the yeast two-hybrid system PMID:11042198 the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other |
| GO:0005515 protein binding | IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine... | REMOVE | Summary: IPI from a high-throughput complex/interactome study recovering IDH1 with IDH2. Reflects genuine co-membership of the NAD-IDH hetero-octamer; removed only because 'protein binding' adds no functional information beyond part_of GO:0045242. Supporting Evidence: PMID:16429126 Proteome survey reveals modularity of the yeast cell machinery. PMID:11042198 the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other |
| GO:0005515 protein binding | IPI PMID:19343713 Micropreparative fractionation of the complexome by blue nat... | REMOVE | Summary: IPI from a high-throughput complex/interactome study recovering IDH1 with IDH2. Reflects genuine co-membership of the NAD-IDH hetero-octamer; removed only because 'protein binding' adds no functional information beyond part_of GO:0045242. Supporting Evidence: PMID:19343713 Micropreparative fractionation of the complexome by blue native continuous elution electrophoresis. PMID:11042198 the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | REMOVE | Summary: IPI from a high-throughput complex/interactome study recovering IDH1 with IDH2. Reflects genuine co-membership of the NAD-IDH hetero-octamer; removed only because 'protein binding' adds no functional information beyond part_of GO:0045242. Supporting Evidence: PMID:37968396 The social and structural architecture of the yeast protein interactome. PMID:11042198 the basic structural/functional unit of yeast isocitrate dehydrogenase is a heterodimer of IDH1 and IDH2 subunits and that each subunit contributes to the isocitrate binding site of the other |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: HDA from a mitochondrial proteomics study detecting IDH1. Consistent with the presequence-dependent mitochondrial import of NAD-IDH subunits. Supporting Evidence: PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimensional separation techniques for mitochondrial proteomics. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: HDA from a mitochondrial proteomics study detecting IDH1. Consistent with the presequence-dependent mitochondrial import of NAD-IDH subunits. Supporting Evidence: PMID:24769239 Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER PTN000216786 (NAD-IDH clade, donors include human IDH3A/B/G, Drosophila and both yeast subunits). Mitochondrial location is inherited across the clade and is experimentally established for yeast NAD-IDH. Supporting Evidence: PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization PMID:2198251 Mitochondrial NAD(H)-specific isocitrate dehydrogenase was purified from Saccharomyces cerevisiae for analyses of subunit structure and expression |
| GO:0005739 mitochondrion | IDA PMID:2198251 Subunit structure, expression, and function of NAD(H)-specif... | ACCEPT | Summary: IDA from Keys & McAlister-Henn 1990: NAD-IDH purified from yeast mitochondria; mitochondria from idh1/idh2 mutants lose isocitrate-dependent respiration. Supporting Evidence: PMID:2198251 Mitochondrial NAD(H)-specific isocitrate dehydrogenase was purified from Saccharomyces cerevisiae for analyses of subunit structure and expression PMID:2198251 Mitochondria isolated from the IDH1 and IDH2 mutants exhibited a markedly reduced capacity for utilization of either isocitrate or citrate for respiratory O2 consumption |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (SL-0173, Mitochondrion). Correct. Supporting Evidence: file:yeast/IDH1/IDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005739 mitochondrion | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways TCA-EUK-PWY placing the NAD-IDH reaction in mitochondria. Correct. Supporting Evidence: PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-SCE-1252255 | REMOVE | Summary: TAS from Reactome R-SCE-1252255 (TOM40:TOM70 import into the intermembrane space), an orthology-projected import reaction that lists IDH1 as a cargo. Yeast IDH1 is a presequence-targeted matrix protein; the IMS is at most a transit location during import and is not where the protein resides or functions. Supporting Evidence: PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization file:yeast/IDH1/IDH1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0005759 mitochondrial matrix | IDA PMID:8626605 Assembly and function of a cytosolic form of NADH-specific i... | ACCEPT | Summary: IDA from Zhao & McAlister-Henn 1996: each NAD-IDH subunit depends on its own presequence for import into mitochondria, where the enzyme functions in the matrix TCA cycle. Supporting Evidence: PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005829 cytosol | TAS Reactome:R-SCE-1252255 | REMOVE | Summary: TAS from Reactome R-SCE-1252255 (precursor in the cytosol before TOM import). A cytosolic precursor pool is transit, not a functional location. Cytosolic IDH holoenzyme was only observed when presequences were deleted experimentally; the native enzyme is mitochondrial. Supporting Evidence: PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization PMID:8626605 an active holoenzyme can be assembled in the cytosol and this ''cytosolic'' form of isocitrate dehydrogenase can reverse the acetate- growth phenotype |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER PTN000216786 (NAD-IDH clade; donors include human IDH3, fly, S. pombe and both S. cerevisiae subunits). TCA-cycle participation is the ancestral and conserved role of this clade. Supporting Evidence: PMID:2198251 Mitochondria isolated from the IDH1 and IDH2 mutants exhibited a markedly reduced capacity for utilization of either isocitrate or citrate for respiratory O2 consumption |
| GO:0006099 tricarboxylic acid cycle | IDA PMID:11714283 Kinetic and physiological effects of alterations in homologo... | ACCEPT | Summary: IDA from Lin et al. 2001: site-directed variants of IDH1 alter IDH activity, and activity level correlates with growth on acetate/glycerol, i.e. TCA-cycle-dependent respiratory growth. Supporting Evidence: PMID:11714283 Results indicate a positive correlation between the level of IDH catalytic activity and the ability of cells to grow with acetate or glycerol as carbon sources PMID:11714283 Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from ARBA00033498 and InterPro IPR004434 (NAD-dependent IDH). Correct for this NAD-IDH subunit. Supporting Evidence: PMID:2198251 Mitochondria isolated from the IDH1 and IDH2 mutants exhibited a markedly reduced capacity for utilization of either isocitrate or citrate for respiratory O2 consumption |
| GO:0006099 tricarboxylic acid cycle | TAS PMID:9175438 Molecular genetics of yeast TCA cycle isozymes. | ACCEPT | Summary: TAS from the McAlister-Henn & Small 1997 review of yeast TCA-cycle isozymes. NAD-IDH catalyses the oxidative decarboxylation of isocitrate in the mitochondrial TCA cycle. Supporting Evidence: PMID:9175438 Molecular genetics of yeast TCA cycle isozymes. PMID:2198251 Mitochondria isolated from the IDH1 and IDH2 mutants exhibited a markedly reduced capacity for utilization of either isocitrate or citrate for respiratory O2 consumption |
| GO:0006102 isocitrate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PANTHER PTN000216787 (donors include Arabidopsis IDH subunits and both yeast subunits). NAD-IDH acts on isocitrate; correct though more general than the TCA-cycle process. Supporting Evidence: PMID:11714283 Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP |
| GO:0006102 isocitrate metabolic process | IDA PMID:16884682 Novel allosteric properties produced by residue substitution... | ACCEPT | Summary: IDA from Hu & McAlister-Henn 2006 kinetic analyses of isocitrate oxidation by the purified hetero-octamer. Supporting Evidence: PMID:16884682 Yeast NAD+-specific isocitrate dehydrogenase (IDH) is an octamer of four IDH1 and four IDH2 subunits, and the basic structural unit of the enzyme is an IDH1/IDH2 heterodimer |
| GO:0009060 aerobic respiration | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways TCA-EUK-PWY ('TCA cycle, aerobic respiration'). The TCA cycle is part of aerobic respiration in GO; NAD-IDH is required for isocitrate/citrate-driven respiratory O2 consumption. Supporting Evidence: PMID:2198251 Mitochondria isolated from the IDH1 and IDH2 mutants exhibited a markedly reduced capacity for utilization of either isocitrate or citrate for respiratory O2 consumption |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: IEA from InterPro IPR019818 (family signature shared with the catalytic subunit) asserting an oxidoreductase activity. IDH1 is the regulatory, essentially non-catalytic subunit; it contributes to, but does not itself enable, the oxidoreductase activity. Supporting Evidence: PMID:11042198 IDH2 was previously shown to contain the catalytic site, whereas IDH1 contributes regulatory properties including cooperativity with respect to isocitrate and allosteric activation by AMP PMID:11714283 Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP |
| GO:0042645 mitochondrial nucleoid | IDA PMID:15692048 Aconitase couples metabolic regulation to mitochondrial DNA ... | KEEP AS NON CORE | Summary: IDA from Chen et al. 2005 identifying mtDNA nucleoid-associated proteins (abstract-only in cache; IDH1 not named in the abstract). Several TCA enzymes (Aco1, Kgd1/2, Lsc1, Idh1) were recovered with nucleoids; deferring to the curator who read the full text. A nucleoid association is not part of IDH1's catalytic/regulatory role. Supporting Evidence: PMID:15692048 We have identified 22 mtDNA-associated proteins in yeast, among which is mitochondrial aconitase (Aco1p) |
| GO:0045242 isocitrate dehydrogenase complex (NAD+) | IDA PMID:16884682 Novel allosteric properties produced by residue substitution... | ACCEPT | Summary: IDA from Hu & McAlister-Henn 2006: gel filtration and sedimentation show the octamer of four IDH1 and four IDH2 subunits. Supporting Evidence: PMID:16884682 Yeast NAD+-specific isocitrate dehydrogenase (IDH) is an octamer of four IDH1 and four IDH2 subunits, and the basic structural unit of the enzyme is an IDH1/IDH2 heterodimer |
| GO:0045242 isocitrate dehydrogenase complex (NAD+) | IPI PMID:18256028 Allosteric motions in structures of yeast NAD+-specific isoc... | ACCEPT | Summary: IPI from Taylor et al. 2008 crystal structures of the IDH1/IDH2 hetero-octamer. Supporting Evidence: PMID:18256028 The structures reveal the molecular basis for ligand binding to homologous but distinct regulatory and catalytic sites positioned at the interfaces between IDH1 and IDH2 subunits |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: IEA from InterPro IPR019818 (family signature). The IDH1 site binds isocitrate and AMP as the allosteric regulatory site; NAD+ binding is a property of the catalytic IDH2 site. NAD binding by IDH1 itself is not established and this transfer from the family signature is likely over-reaching. Supporting Evidence: PMID:11714283 Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP PMID:18256028 The structures reveal the molecular basis for ligand binding to homologous but distinct regulatory and catalytic sites positioned at the interfaces between IDH1 and IDH2 subunits |
| GO:0097054 L-glutamate biosynthetic process | TAS PMID:9175438 Molecular genetics of yeast TCA cycle isozymes. | KEEP AS NON CORE | Summary: TAS from the McAlister-Henn & Small 1997 review. NAD-IDH produces 2-oxoglutarate, the carbon skeleton for glutamate synthesis, so it acts upstream of glutamate biosynthesis rather than catalysing a step of it; NADP-dependent isozymes (IDP1/2/3) also supply 2-oxoglutarate. Retained as non-core context. Supporting Evidence: PMID:9175438 Molecular genetics of yeast TCA cycle isozymes. file:yeast/IDH1/IDH1-uniprot.txt Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH; |
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Subunit of mitochondrial NAD(+)-dependent isocitrate dehydrogenase; complex catalyzes the oxidation of isocitrate to alpha-ketoglutarate in the TCA cycle
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