Catalytic subunit (Idh2p, YOR136W) of the mitochondrial NAD+-dependent isocitrate dehydrogenase (NAD-IDH, EC 1.1.1.41), a hetero-octamer of four Idh1 and four Idh2 subunits built from Idh1/Idh2 heterodimers. Idh2 contains the catalytic isocitrate/Mg2+ site where isocitrate is oxidatively decarboxylated to 2-oxoglutarate with reduction of NAD+ to NADH, a rate-limiting step of the TCA cycle in the mitochondrial matrix; the homologous Idh1 subunit provides allosteric regulation by AMP and isocitrate cooperativity. Both subunits are required for activity; loss of NAD-IDH abolishes isocitrate-driven mitochondrial respiration and impairs growth on acetate and glycerol. The Idh1/Idh2 enzyme also binds specifically to the 5'-untranslated leaders of mitochondrial mRNAs, and such transcripts inhibit its catalytic activity in vitro in a way that AMP relieves; any effect of IDH on mitochondrial translation appears to be indirect.
| 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). The divalent metal (Mg2+/Mn2+) that bridges isocitrate in the IDH2 catalytic site is a genuine cofactor requirement of this subunit; metal binding is a cofactor property rather than the core activity. Supporting Evidence: file:yeast/IDH2/IDH2-uniprot.txt Note=Binds 1 Mg(2+) or Mn(2+) ion per subunit. 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: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: kinetic analyses of purified IDH1/IDH2 hetero-octamers. IDH2 carries the catalytic isocitrate site, but activity requires the IDH1/IDH2 heterodimer, so contributes_to is an appropriate 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 | ACCEPT | Summary: IEA from Rhea/EC 1.1.1.41 mapping. IDH2 is the catalytic subunit of NAD+-dependent isocitrate dehydrogenase; residue substitutions in the IDH2 isocitrate site reduce Vmax 30->300-fold. Supporting Evidence: file:yeast/IDH2/IDH2-uniprot.txt Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH; 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:0004449 isocitrate dehydrogenase (NAD+) activity | RCA GO_REF:0000123 | ACCEPT | Summary: RCA from YeastPathways TCA-EUK-PWY (isocitrate + NAD+ -> 2-oxoglutarate + CO2 + NADH). Correct for the catalytic IDH2 subunit; contributes_to reflects the obligate heteromeric enzyme. 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/IDH2/IDH2-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 IDH2-IDH1 interaction (two-hybrid and mutational analysis). The interaction is real and obligate (IDH2 and IDH1 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 IDH2 with IDH1. 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 IDH2 with IDH1. 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 IDH2 with IDH1. 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:11914276 Subcellular localization of the yeast proteome. | ACCEPT | Summary: HDA from a mitochondrial proteomics study detecting IDH2. Consistent with the presequence-dependent mitochondrial import of NAD-IDH subunits. Supporting Evidence: PMID:11914276 Subcellular localization of the yeast proteome. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005739 mitochondrion | HDA PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria. | ACCEPT | Summary: HDA from a mitochondrial proteomics study detecting IDH2. Consistent with the presequence-dependent mitochondrial import of NAD-IDH subunits. Supporting Evidence: PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: HDA from a mitochondrial proteomics study detecting IDH2. 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 IDH2. 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:11502169 Yeast mitochondrial dehydrogenases are associated in a supra... | ACCEPT | Summary: IDA from Grandier-Vazeille et al. 2001 (native-gel analysis of mitochondrial dehydrogenase supercomplexes; abstract-only in cache and IDH2 is not named in the abstract). Mitochondrial localisation of IDH2 is independently well established; deferring to the curator. Supporting Evidence: PMID:11502169 Yeast mitochondrial dehydrogenases are associated in a supramolecular complex. PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| 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 | 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:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (SL-0170, Mitochondrion matrix). Correct; NAD-IDH is a matrix TCA-cycle enzyme. Supporting Evidence: file:yeast/IDH2/IDH2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix PMID:8626605 Each subunit was found to be dependent upon its presequence for mitochondrial localization |
| 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 IDH2 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:0000002 | ACCEPT | Summary: IEA from InterPro IPR004434 (NAD-dependent isocitrate dehydrogenase) mapping. 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 | MODIFY | Summary: IEA from InterPro IPR019818 to the broad parent 'oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor'. Correct but uninformative; the specific activity of the catalytic IDH2 subunit is isocitrate dehydrogenase (NAD+) activity. Proposed replacements: isocitrate dehydrogenase (NAD+) activity Supporting Evidence: file:yeast/IDH2/IDH2-uniprot.txt Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH; 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: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 | KEEP AS NON CORE | Summary: IEA from InterPro IPR019818. IDH2 carries the catalytic site and must bind the NAD+ cofactor; NAD+ binding by the enzyme was measured directly. Cofactor binding is subsidiary to the catalytic activity. Supporting Evidence: PMID:16884682 These allosteric properties are also apparent in NAD+-binding experiments 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: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/IDH2/IDH2-uniprot.txt Reaction=D-threo-isocitrate + NAD(+) = 2-oxoglutarate + CO2 + NADH; |
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Download this section (compressed HTML)Subunit of mitochondrial NAD(+)-dependent isocitrate dehydrogenase; complex catalyzes oxidation of isocitrate to alpha-ketoglutarate in TCA cycle; targeted to vacuole via AP-3 pathway
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