Mitochondrial homoisocitrate dehydrogenase (EC 1.1.1.87) of Saccharomyces cerevisiae, a member of the isocitrate/isopropylmalate dehydrogenase family. Lys12 catalyses the NAD+- and Mg2+-dependent oxidative decarboxylation of (2R,3S)-homoisocitrate to 2-oxoadipate (alpha-ketoadipate), step 4 of the alpha-aminoadipate pathway of lysine biosynthesis. It follows a steady-state random kinetic mechanism with the Mg-homoisocitrate complex as substrate and discriminates strongly against isocitrate. Lys12 has an N-terminal mitochondrial targeting signal and is located in mitochondria, together with the preceding homoaconitase steps; it also carries a C-terminal PTS1-like sequence, but it has not been seen in peroxisomes. Its expression is repressed by lysine.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro (isocitrate/isopropylmalate dehydrogenase family) mapping to magnesium ion binding. Correct for Lys12: kinetic work shows the Mg-homoisocitrate complex is the substrate and UniProt records one Mg2+ per subunit. A cofactor-binding property, not the core function. Supporting Evidence: PMID:17223711 Initial velocity data indicate the MgHIc complex is the reactant in the direction of oxidative decarboxylation |
| GO:0005739 mitochondrion | HDA PMID:11914276 Subcellular localization of the yeast proteome. | ACCEPT | Summary: Genome-wide immunolocalisation placed Lys12 in mitochondria, consistent with its N-terminal mitochondrial targeting signal and the GFP data. Supporting Evidence: PMID:11914276 By high-throughput immunolocalization of tagged gene products, we have determined the subcellular localization of 2744 yeast proteins. PMID:28928432 This putative PTS1 is conserved in related yeast species, but Lys12p also contains a typical N-terminal mitochondrial targeting signal (MTS) and Lys12p-GFP localises to mitochondria |
| GO:0005739 mitochondrion | HDA PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria. | ACCEPT | Summary: Lys12 was identified in the proteome of highly purified mitochondria (Sickmann et al. 2003). Consistent with its MTS and other localisation data. Supporting Evidence: PMID:14576278 The proteins of highly pure yeast mitochondria were separated by several independent methods and analyzed by tandem MS. |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: Lys12 detected in the PROMITO mitochondrial proteome. Consistent with its mitochondrial targeting. Supporting Evidence: PMID:16823961 A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: Lys12 quantified in isolated mitochondria grown on fermentable and respiratory carbon sources. Consistent with its mitochondrial localisation. Supporting Evidence: PMID:24769239 we performed an overall quantitative proteomic and phosphoproteomic study of isolated mitochondria extracted from yeast grown on fermentative (glucose or galactose) and respiratory (lactate) media |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial activity for fungal homoisocitrate dehydrogenases. Lys12 has an N-terminal MTS and is found in mitochondria by GFP tagging and organelle proteomics; the homoaconitase (Lys4) and Aco2 steps that feed it are mitochondrial too. Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion PMID:28928432 This putative PTS1 is conserved in related yeast species, but Lys12p also contains a typical N-terminal mitochondrial targeting signal (MTS) and Lys12p-GFP localises to mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location (Mitochondrion, from PMID:14562095/14576278) mapped to GO. Correct. Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion PMID:28928432 This putative PTS1 is conserved in related yeast species, but Lys12p also contains a typical N-terminal mitochondrial targeting signal (MTS) and Lys12p-GFP localises to mitochondria |
| GO:0005829 cytosol | RCA GO_REF:0000123 | MODIFY | Summary: RCA from YeastPathways LYSINE-AMINOAD-PWY-2, which assigns cytosol to every pathway enzyme. Lys12 is a mitochondrial enzyme (MTS; GFP and proteomic localisation; GFP-Lys12 is cytosolic only when an N-terminal tag disrupts the MTS). The cytosol assignment is a pathway-diagram default and should be replaced by mitochondrion. Proposed replacements: mitochondrion Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion PMID:28928432 This putative PTS1 is conserved in related yeast species, but Lys12p also contains a typical N-terminal mitochondrial targeting signal (MTS) and Lys12p-GFP localises to mitochondria PMID:28928432 The N-terminal tag does interfere with the mitochondrial targeting signal of Lys12p, hence GFP-Lys12p mislocalised to the cytosol |
| GO:0009085 L-lysine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of lysine biosynthesis for the fungal homoisocitrate dehydrogenase clade. Lys12 catalyses step 4 of the alpha-aminoadipate pathway (homoisocitrate -> 2-oxoadipate). Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt pathway; L-alpha-aminoadipate from 2-oxoglutarate: step 4/5. PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies |
| GO:0009085 L-lysine biosynthetic process | IC PMID:17223711 Complete kinetic mechanism of homoisocitrate dehydrogenase f... | ACCEPT | Summary: Curator inference from the demonstrated homoisocitrate dehydrogenase activity (with/from GO:0047046): this reaction exists only in the alpha-aminoadipate lysine pathway, so the enzyme participates in lysine biosynthesis. Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt pathway; L-alpha-aminoadipate from 2-oxoglutarate: step 4/5. PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies |
| GO:0009085 L-lysine biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways LYSINE-AMINOAD-PWY-2 assigns the homoisocitrate dehydrogenase step to Lys12. Correct. Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt pathway; L-alpha-aminoadipate from 2-oxoglutarate: step 4/5. PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-derived parent term (oxidoreductase acting on CH-OH donors with NAD/NADP). True but uninformative; the specific activity, homoisocitrate dehydrogenase (an is_a descendant), is experimentally established. Proposed replacements: homoisocitrate dehydrogenase activity Supporting Evidence: PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies PMID:17223711 Isocitrate is a slow substrate with a rate (V/E(t)) 216-fold slower than that measured with HIc. file:yeast/LYS12/LYS12-uniprot.txt Catalyzes the NAD(+)-dependent conversion of homoisocitrate |
| GO:0047046 homoisocitrate dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of homoisocitrate dehydrogenase activity for the fungal clade within the isocitrate/isopropylmalate dehydrogenase family. Lys12 has its own direct kinetic evidence. Supporting Evidence: PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies PMID:17223711 Isocitrate is a slow substrate with a rate (V/E(t)) 216-fold slower than that measured with HIc. file:yeast/LYS12/LYS12-uniprot.txt Catalyzes the NAD(+)-dependent conversion of homoisocitrate |
| GO:0047046 homoisocitrate dehydrogenase activity | IDA PMID:17223711 Complete kinetic mechanism of homoisocitrate dehydrogenase f... | ACCEPT | Summary: Complete kinetic mechanism determined for purified S. cerevisiae homoisocitrate dehydrogenase (steady-state random mechanism, Mg-homoisocitrate as substrate); isocitrate is a poor alternative substrate (216-fold slower), confirming homoisocitrate specificity. Supporting Evidence: PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies PMID:17223711 Isocitrate is a slow substrate with a rate (V/E(t)) 216-fold slower than that measured with HIc. file:yeast/LYS12/LYS12-uniprot.txt Catalyzes the NAD(+)-dependent conversion of homoisocitrate |
| GO:0047046 homoisocitrate dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA from InterPro/Rhea:11900/EC 1.1.1.87 matching the characterised reaction. Correct. Supporting Evidence: PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies PMID:17223711 Isocitrate is a slow substrate with a rate (V/E(t)) 216-fold slower than that measured with HIc. file:yeast/LYS12/LYS12-uniprot.txt Catalyzes the NAD(+)-dependent conversion of homoisocitrate |
| GO:0047046 homoisocitrate dehydrogenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways assignment of the homoisocitrate -> 2-oxoadipate reaction to Lys12. Correct. Supporting Evidence: PMID:17223711 The kinetic mechanism of homoisocitrate dehydrogenase from Saccharomyces cerevisiae was determined using initial velocity studies PMID:17223711 Isocitrate is a slow substrate with a rate (V/E(t)) 216-fold slower than that measured with HIc. file:yeast/LYS12/LYS12-uniprot.txt Catalyzes the NAD(+)-dependent conversion of homoisocitrate |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro mapping to NAD binding. Correct for this NAD+-dependent dehydrogenase (NADH is a product inhibitor), but it is a cofactor property implied by the core activity. Supporting Evidence: file:yeast/LYS12/LYS12-uniprot.txt ACTIVITY REGULATION: Inhibited by the reaction product NADH. |
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