Minor 2-isopropylmalate synthase (alpha-isopropylmalate synthase II, alpha-IPMS, EC 2.3.3.13) of Saccharomyces cerevisiae, a paralog of Leu4 arising from the whole-genome duplication. Leu9 condenses acetyl-CoA with 3-methyl-2-oxobutanoate (alpha-ketoisovalerate) to give 2-isopropylmalate, the first committed step of leucine biosynthesis, in mitochondria. Leu9 accounts for the residual ~20% of alpha-IPMS activity in leu4 mutants; unlike Leu4, the Leu9 homodimer is resistant to leucine feedback inhibition, and Leu4-Leu9 heterodimers formed in vivo have intermediate leucine sensitivity. leu9 single deletions have no obvious phenotype, while leu4 leu9 double mutants lack alpha-IPMS activity and are leucine auxotrophs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Root catalytic activity from InterPro. True but uninformative. Reason: Replace with the specific activity. Proposed replacements: 2-isopropylmalate synthase activity Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (seeded by Leu4 and Leu9). Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | IDA PMID:11158296 The yeast mitochondrial carrier Leu5p and its human homologu... | ACCEPT | Summary: Mitochondrial alpha-IPMS activity measured in a study of the CoA carrier Leu5 (full text not available; deferring to the curator). Activity is independently established. Core. Supporting Evidence: PMID:11158296 the activities of several mitochondrial CoA-dependent enzymes were strongly decreased in Deltaleu5 cells PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | IDA PMID:25841022 Diversification of Paralogous Ξ±-Isopropylmalate Synthases by... | ACCEPT | Summary: Purified Leu9 homodimer has alpha-IPMS activity that is leucine resistant. Core. Supporting Evidence: PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic EC/RHEA mapping. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | IGI PMID:10790691 Identification by functional analysis of the gene encoding a... | ACCEPT | Summary: Genetic interaction with LEU4: YOR108w restores alpha-IPMS activity to a leu4 leu9 double mutant. Core. Supporting Evidence: PMID:10790691 A mutant in which both ORF YOR108w and LEU4 gene have been deleted proved to be leucine auxotrophic and alpha-isopropylmalate synthase (alpha-IPMS)-negative. PMID:10790691 This mutant recovered alpha-IPMS activity and a Leu(+) phenotype when transformed with a plasmid copy of YOR108w. |
| GO:0003852 2-isopropylmalate synthase activity | ISS PMID:10790691 Identification by functional analysis of the gene encoding a... | ACCEPT | Summary: Sequence similarity to Leu4 (ISS) supported by functional complementation. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. |
| GO:0003852 2-isopropylmalate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways BCAA superpathway assignment. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0003852 2-isopropylmalate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways leucine biosynthesis assignment. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0005515 protein binding | IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine... | MODIFY | Summary: High-throughput detection of Leu9-Leu4 interaction; real but uninformative term. Reason: The interaction partner is the paralogous alpha-IPMS (Leu4/Leu9); Lopez et al. 2015 showed these form heterodimeric isozymes in vivo, so the informative term is protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:16429126 Proteome survey reveals modularity of the yeast cell machinery. PMID:25841022 Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. |
| GO:0005515 protein binding | IPI PMID:18719252 High-quality binary protein interaction map of the yeast int... | MODIFY | Summary: Yeast two-hybrid Leu9-Leu4 interaction; real but uninformative term. Reason: The interaction partner is the paralogous alpha-IPMS (Leu4/Leu9); Lopez et al. 2015 showed these form heterodimeric isozymes in vivo, so the informative term is protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:18719252 demonstrating that high-throughput yeast two-hybrid (Y2H) screening provides high-quality binary interaction information PMID:25841022 Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. |
| GO:0005515 protein binding | IPI PMID:25841022 Diversification of Paralogous Ξ±-Isopropylmalate Synthases by... | MODIFY | Summary: Direct BiFC and co-purification evidence for Leu4-Leu9 heterodimeric isozymes with distinct regulation. Better captured as protein heterodimerization activity. Reason: Replace generic protein binding with the specific heteromeric association documented. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:25841022 Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | MODIFY | Summary: High-throughput interactome detection of Leu9-Leu4; real but uninformative term. Reason: The interaction partner is the paralogous alpha-IPMS (Leu4/Leu9); Lopez et al. 2015 showed these form heterodimeric isozymes in vivo, so the informative term is protein heterodimerization activity. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:37968396 The social and structural architecture of the yeast protein interactome. PMID:25841022 Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: Mitochondrial proteome HDA. Core location. Supporting Evidence: PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimensional separation techniques for mitochondrial proteomics. PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: Mitochondrial proteome HDA. Core location. Supporting Evidence: PMID:24769239 Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae. PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (is_active_in mitochondrion). Core location. Supporting Evidence: PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria PMID:25841022 Ξ±-IPM is then transported from the mitochondria to the cytosol by the yeast oxaloacetate/sulfate carrier Oac1 |
| GO:0005739 mitochondrion | IDA PMID:11158296 The yeast mitochondrial carrier Leu5p and its human homologu... | ACCEPT | Summary: Mitochondrial localization/activity in a Leu5 carrier study (deferring to the curator on full text); consistent with direct localization by Lopez et al. 2015. Supporting Evidence: PMID:11158296 the activities of several mitochondrial CoA-dependent enzymes were strongly decreased in Deltaleu5 cells PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic mitochondrion annotation; correct. Supporting Evidence: PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria |
| GO:0005829 cytosol | RCA GO_REF:0000123 | REMOVE | Summary: YeastPathways places the alpha-IPMS step in the cytosol, and this is propagated to Leu9. Unlike LEU4, LEU9 has no documented cytosolic (short) form; Leu9 has a mitochondrial presequence and is localized to mitochondria, where alpha-isopropylmalate is made before export to the cytosol by Oac1. Reason: Compartment assignment of the pathway step to cytosol is not applicable to Leu9, a mitochondrial-only isozyme. Supporting Evidence: PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria PMID:25841022 Ξ±-IPM is then transported from the mitochondria to the cytosol by the yeast oxaloacetate/sulfate carrier Oac1 |
| GO:0005829 cytosol | RCA GO_REF:0000123 | REMOVE | Summary: As above: cytosolic placement from YeastPathways is incorrect for the mitochondrial-only Leu9. Reason: Leu9 is mitochondrial; no cytosolic form documented. Supporting Evidence: PMID:25841022 Subcellular localization analysis showed that Leu4 and Leu9 are localized in the mitochondria PMID:25841022 Ξ±-IPM is then transported from the mitochondria to the cytosol by the yeast oxaloacetate/sulfate carrier Oac1 |
| GO:0008270 zinc ion binding | RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr... | KEEP AS NON CORE | Summary: Zinc binding inferred in a computational zinc-proteome survey. Reason: The zinc assignment is from a bioinformatic zinc-proteome survey; LeuA-family synthases bind a catalytic divalent metal, but the physiological metal of the yeast enzyme has not been established. Kept as a plausible non-core cofactor annotation. Supporting Evidence: PMID:30358795 The yeast zinc proteome of 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis that combined global domain searches with local motif searches. |
| GO:0009082 branched-chain amino acid biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: Correct parent of leucine biosynthesis. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. |
| GO:0009098 L-leucine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. PMID:10790691 A mutant in which both ORF YOR108w and LEU4 gene have been deleted proved to be leucine auxotrophic and alpha-isopropylmalate synthase (alpha-IPMS)-negative. |
| GO:0009098 L-leucine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation consistent with experimental data. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. |
| GO:0009098 L-leucine biosynthetic process | IGI PMID:10790691 Identification by functional analysis of the gene encoding a... | ACCEPT | Summary: leu4 leu9 double deletion is leucine auxotrophic; Leu9 complements. Core. Supporting Evidence: PMID:10790691 A mutant in which both ORF YOR108w and LEU4 gene have been deleted proved to be leucine auxotrophic and alpha-isopropylmalate synthase (alpha-IPMS)-negative. |
| GO:0009098 L-leucine biosynthetic process | IMP PMID:25841022 Diversification of Paralogous Ξ±-Isopropylmalate Synthases by... | ACCEPT | Summary: Mutant analysis of the paralogous alpha-IPMSs in leucine biosynthesis (Lopez et al. 2015). Core. Supporting Evidence: PMID:25841022 The budding yeast Saccharomyces cerevisiae has two paralogous genes, LEU4 and LEU9, that encode Ξ±-IPM synthase (Ξ±-IPMS) isozymes. PMID:25841022 Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. |
| GO:0009098 L-leucine biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways leucine biosynthesis. Core. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. |
| GO:0046912 acyltransferase activity, acyl groups converted into alkyl on transfer | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro-based parent class of 2-isopropylmalate synthase activity; correct but less specific. Reason: Redundant with the specific activity term. Supporting Evidence: PMID:10790691 These data and the sequence homology indicated that YOR108w is the structural gene for alpha-IPMS II, responsible for the residual alpha-IPMS activity found in a leu4Delta strain. |
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Download this section (compressed HTML)Alpha-isopropylmalate synthase II (2-isopropylmalate synthase); catalyzes the first step in the leucine biosynthesis pathway; the minor isozyme, responsible for the residual alpha-IPMS activity detected in a leu4 null mutant; LEU9 has a paralog, LEU4, that arose from the whole genome duplication
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