ID ACON_YEAST Reviewed; 778 AA. AC P19414; D6VYU7; DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 2. DT 02-DEC-2020, entry version 197. DE RecName: Full=Aconitate hydratase, mitochondrial; DE Short=Aconitase; DE EC=4.2.1.3 {ECO:0000269|PubMed:1972545}; DE AltName: Full=Citrate hydro-lyase; DE Flags: Precursor; GN Name=ACO1; Synonyms=GLU1; OrderedLocusNames=YLR304C; ORFNames=L8003.22; OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast). OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; OC Saccharomycetales; Saccharomycetaceae; Saccharomyces. OX NCBI_TaxID=559292; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND RP CATALYTIC ACTIVITY. RC STRAIN=ATCC 44774 / DBY747; RX PubMed=1972545; DOI=10.1128/mcb.10.7.3551; RA Gangloff S.P., Marguet D., Lauquin G.J.-M.; RT "Molecular cloning of the yeast mitochondrial aconitase gene (ACO1) and RT evidence of a synergistic regulation of expression by glucose plus RT glutamate."; RL Mol. Cell. Biol. 10:3551-3561(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 204508 / S288c; RX PubMed=9169871; RA Johnston M., Hillier L.W., Riles L., Albermann K., Andre B., Ansorge W., RA Benes V., Brueckner M., Delius H., Dubois E., Duesterhoeft A., RA Entian K.-D., Floeth M., Goffeau A., Hebling U., Heumann K., RA Heuss-Neitzel D., Hilbert H., Hilger F., Kleine K., Koetter P., Louis E.J., RA Messenguy F., Mewes H.-W., Miosga T., Moestl D., Mueller-Auer S., RA Nentwich U., Obermaier B., Piravandi E., Pohl T.M., Portetelle D., RA Purnelle B., Rechmann S., Rieger M., Rinke M., Rose M., Scharfe M., RA Scherens B., Scholler P., Schwager C., Schwarz S., Underwood A.P., RA Urrestarazu L.A., Vandenbol M., Verhasselt P., Vierendeels F., Voet M., RA Volckaert G., Voss H., Wambutt R., Wedler E., Wedler H., Zimmermann F.K., RA Zollner A., Hani J., Hoheisel J.D.; RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome XII."; RL Nature 387:87-90(1997). RN [3] RP GENOME REANNOTATION. RC STRAIN=ATCC 204508 / S288c; RX PubMed=24374639; DOI=10.1534/g3.113.008995; RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R., RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S., RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.; RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now."; RL G3 (Bethesda) 4:389-398(2014). RN [4] RP PROTEIN SEQUENCE OF 17-23, AND SUBCELLULAR LOCATION. RX PubMed=15975908; DOI=10.1091/mbc.e04-11-1028; RA Regev-Rudzki N., Karniely S., Ben-Haim N.N., Pines O.; RT "Yeast aconitase in two locations and two metabolic pathways: seeing small RT amounts is believing."; RL Mol. Biol. Cell 16:4163-4171(2005). RN [5] RP DISRUPTION PHENOTYPE. RX PubMed=10224250; RA Przybyla-Zawislak B., Gadde D.M., Ducharme K., McCammon M.T.; RT "Genetic and biochemical interactions involving tricarboxylic acid cycle RT (TCA) function using a collection of mutants defective in all TCA cycle RT genes."; RL Genetics 152:153-166(1999). RN [6] RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS]. RX PubMed=14562106; DOI=10.1038/nature02046; RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N., RA O'Shea E.K., Weissman J.S.; RT "Global analysis of protein expression in yeast."; RL Nature 425:737-741(2003). RN [7] RP FUNCTION, AND SUBUNIT. RX PubMed=15692048; DOI=10.1126/science.1106391; RA Chen X.J., Wang X., Kaufman B.A., Butow R.A.; RT "Aconitase couples metabolic regulation to mitochondrial DNA maintenance."; RL Science 307:714-717(2005). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-556, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC STRAIN=ADR376; RX PubMed=17330950; DOI=10.1021/pr060559j; RA Li X., Gerber S.A., Rudner A.D., Beausoleil S.A., Haas W., Villen J., RA Elias J.E., Gygi S.P.; RT "Large-scale phosphorylation analysis of alpha-factor-arrested RT Saccharomyces cerevisiae."; RL J. Proteome Res. 6:1190-1197(2007). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-409, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC STRAIN=ATCC 76625 / YPH499; RX PubMed=17761666; DOI=10.1074/mcp.m700098-mcp200; RA Reinders J., Wagner K., Zahedi R.P., Stojanovski D., Eyrich B., RA van der Laan M., Rehling P., Sickmann A., Pfanner N., Meisinger C.; RT "Profiling phosphoproteins of yeast mitochondria reveals a role of RT phosphorylation in assembly of the ATP synthase."; RL Mol. Cell. Proteomics 6:1896-1906(2007). RN [10] RP FUNCTION, AND SUBUNIT. RX PubMed=17698960; DOI=10.1073/pnas.0703078104; RA Chen X.J., Wang X., Butow R.A.; RT "Yeast aconitase binds and provides metabolically coupled protection to RT mitochondrial DNA."; RL Proc. Natl. Acad. Sci. U.S.A. 104:13738-13743(2007). RN [11] RP DISRUPTION PHENOTYPE. RX PubMed=18359281; DOI=10.1016/j.abb.2008.03.005; RA Lin A.P., Hakala K.W., Weintraub S.T., McAlister-Henn L.; RT "Suppression of metabolic defects of yeast isocitrate dehydrogenase and RT aconitase mutants by loss of citrate synthase."; RL Arch. Biochem. Biophys. 474:205-212(2008). RN [12] RP SUBCELLULAR LOCATION. RX PubMed=18577574; DOI=10.1242/jcs.029207; RA Regev-Rudzki N., Yogev O., Pines O.; RT "The mitochondrial targeting sequence tilts the balance between RT mitochondrial and cytosolic dual localization."; RL J. Cell Sci. 121:2423-2431(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-391, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19779198; DOI=10.1126/science.1172867; RA Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.; RT "Global analysis of Cdk1 substrate phosphorylation sites provides insights RT into evolution."; RL Science 325:1682-1686(2009). RN [14] RP SUBCELLULAR LOCATION. RX PubMed=21440554; DOI=10.1016/j.jmb.2011.03.045; RA Ben-Menachem R., Regev-Rudzki N., Pines O.; RT "The aconitase C-terminal domain is an independent dual targeting RT element."; RL J. Mol. Biol. 409:113-123(2011). RN [15] RP FUNCTION, INDUCTION, AND MUTAGENESIS OF ARG-604. RX PubMed=23106124; DOI=10.1111/mmi.12076; RA Fazius F., Shelest E., Gebhardt P., Brock M.; RT "The fungal alpha-aminoadipate pathway for lysine biosynthesis requires two RT enzymes of the aconitase family for the isomerization of homocitrate to RT homoisocitrate."; RL Mol. Microbiol. 86:1508-1530(2012). RN [16] RP FUNCTION. RX PubMed=24066190; DOI=10.1155/2013/493536; RA Farooq M.A., Pracheil T.M., Dong Z., Xiao F., Liu Z.; RT "Mitochondrial DNA instability in cells lacking aconitase correlates with RT iron citrate toxicity."; RL Oxid. Med. Cell. Longev. 2013:493536-493536(2013). CC -!- FUNCTION: Catalyzes the isomerization of citrate to isocitrate via cis- CC aconitate, a step in the citric acid cycle. Can also provide minor CC contributions to the reversible dehydration of (R)-homocitrate to cis- CC homoaconitate, a step in the alpha-aminoadipate pathway for lysine CC biosynthesis. Plays also an essential role in mtDNA maintenance. May CC directly protect mtDNA from accumulation of point mutations and ssDNA CC breaks as a component of mitochondrial nucleoids, or by preventing CC accumulation of iron citrate thereby alleviating its detrimental CC effects in mitochondria. {ECO:0000269|PubMed:15692048, CC ECO:0000269|PubMed:17698960, ECO:0000269|PubMed:1972545, CC ECO:0000269|PubMed:23106124, ECO:0000269|PubMed:24066190}. CC -!- CATALYTIC ACTIVITY: CC Reaction=citrate = D-threo-isocitrate; Xref=Rhea:RHEA:10336, CC ChEBI:CHEBI:15562, ChEBI:CHEBI:16947; EC=4.2.1.3; CC Evidence={ECO:0000269|PubMed:1972545}; CC -!- COFACTOR: CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; Evidence={ECO:0000250}; CC Note=Binds 1 [4Fe-4S] cluster per subunit. {ECO:0000250}; CC -!- ACTIVITY REGULATION: Subject to catabolite regulation. CC -!- PATHWAY: Carbohydrate metabolism; tricarboxylic acid cycle; isocitrate CC from oxaloacetate: step 2/2. {ECO:0000269|PubMed:1972545}. CC -!- SUBUNIT: Monomer. Binds to mitochondrial DNA (mtDNA) and identified as CC component of mitochondrial nucleoids. {ECO:0000269|PubMed:15692048, CC ECO:0000269|PubMed:17698960}. CC -!- SUBCELLULAR LOCATION: Mitochondrion. Cytoplasm. Note=Mainly CC mitochondrial, small amounts are also detected in the cytosol with a CC ratio of 94:6. CC -!- INDUCTION: Highly induced in the absence of glutamate. Induction is CC further increased when both glutamate and lysine are missing. CC {ECO:0000269|PubMed:23106124}. CC -!- DISRUPTION PHENOTYPE: Essential for growth on nonfermentable carbon CC sources and for biosynthesis of glutamate. Causes a dramatic increase CC in cellular citrate levels. {ECO:0000269|PubMed:10224250, CC ECO:0000269|PubMed:18359281, ECO:0000269|PubMed:1972545}. CC -!- MISCELLANEOUS: The fermenting yeast S.cerevisiae has 2 aconitases, ACO1 CC essential for the citric acid cycle, and ACO2 specifically and CC exclusively contributing to lysine biosynthesis. In contrast, in CC respiring filamentous fungi the ACO2 homologs (acoB) seem enzymatically CC inactive and the ACO1 homolog (acoA) is solely responsible for these CC functions. CC -!- MISCELLANEOUS: Present with 96700 molecules/cell in log phase SD CC medium. {ECO:0000269|PubMed:14562106}. CC -!- SIMILARITY: Belongs to the aconitase/IPM isomerase family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M33131; AAA34389.1; -; Genomic_DNA. DR EMBL; U17243; AAB67348.1; -; Genomic_DNA. DR EMBL; BK006945; DAA09613.1; -; Genomic_DNA. DR PIR; S50387; S50387. DR RefSeq; NP_013407.1; NM_001182192.1. DR SMR; P19414; -. DR BioGRID; 31569; 213. DR DIP; DIP-4679N; -. DR IntAct; P19414; 33. DR MINT; P19414; -. DR STRING; 4932.YLR304C; -. DR MoonDB; P19414; Curated. DR iPTMnet; P19414; -. DR MaxQB; P19414; -. DR PaxDb; P19414; -. DR PRIDE; P19414; -. DR TopDownProteomics; P19414; -. DR EnsemblFungi; YLR304C_mRNA; YLR304C; YLR304C. DR GeneID; 851013; -. DR KEGG; sce:YLR304C; -. DR EuPathDB; FungiDB:YLR304C; -. DR SGD; S000004295; ACO1. DR eggNOG; KOG0453; Eukaryota. DR GeneTree; ENSGT00940000154892; -. DR HOGENOM; CLU_006714_2_2_1; -. DR InParanoid; P19414; -. DR OMA; GRASYMR; -. DR BioCyc; MetaCyc:YLR304C-MONOMER; -. DR Reactome; R-SCE-71403; Citric acid cycle (TCA cycle). DR UniPathway; UPA00223; UER00718. DR PRO; PR:P19414; -. DR Proteomes; UP000002311; Chromosome XII. DR RNAct; P19414; protein. DR GO; GO:0005829; C:cytosol; IDA:SGD. DR GO; GO:0005758; C:mitochondrial intermembrane space; TAS:Reactome. DR GO; GO:0005759; C:mitochondrial matrix; IDA:SGD. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:SGD. DR GO; GO:0005739; C:mitochondrion; HDA:SGD. DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IBA:GO_Central. DR GO; GO:0003994; F:aconitate hydratase activity; IDA:SGD. DR GO; GO:0047780; F:citrate dehydratase activity; IEA:UniProtKB-EC. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:SGD. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:SGD. DR GO; GO:0000002; P:mitochondrial genome maintenance; IMP:SGD. DR GO; GO:0006099; P:tricarboxylic acid cycle; IDA:SGD. DR Gene3D; 3.20.19.10; -; 1. DR Gene3D; 3.30.499.10; -; 2. DR Gene3D; 3.40.1060.10; -; 1. DR InterPro; IPR015931; Acnase/IPM_dHydase_lsu_aba_1/3. DR InterPro; IPR001030; Acoase/IPM_deHydtase_lsu_aba. DR InterPro; IPR015928; Aconitase/3IPM_dehydase_swvl. DR InterPro; IPR018136; Aconitase_4Fe-4S_BS. DR InterPro; IPR036008; Aconitase_4Fe-4S_dom. DR InterPro; IPR015932; Aconitase_dom2. DR InterPro; IPR006248; Aconitase_mito-like. DR InterPro; IPR000573; AconitaseA/IPMdHydase_ssu_swvl. DR Pfam; PF00330; Aconitase; 1. DR Pfam; PF00694; Aconitase_C; 1. DR PRINTS; PR00415; ACONITASE. DR SUPFAM; SSF53732; SSF53732; 1. DR TIGRFAMs; TIGR01340; aconitase_mito; 1. DR PROSITE; PS00450; ACONITASE_1; 1. DR PROSITE; PS01244; ACONITASE_2; 1. PE 1: Evidence at protein level; KW 4Fe-4S; Cytoplasm; Direct protein sequencing; Iron; Iron-sulfur; Lyase; KW Metal-binding; Mitochondrion; Phosphoprotein; Reference proteome; KW Transit peptide; Tricarboxylic acid cycle. FT TRANSIT 1..16 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:15975908" FT CHAIN 17..778 FT /note="Aconitate hydratase, mitochondrial" FT /id="PRO_0000000547" FT REGION 188..190 FT /note="Substrate binding" FT /evidence="ECO:0000250" FT REGION 667..668 FT /note="Substrate binding" FT /evidence="ECO:0000250" FT METAL 382 FT /note="Iron-sulfur (4Fe-4S)" FT /evidence="ECO:0000250" FT METAL 445 FT /note="Iron-sulfur (4Fe-4S)" FT /evidence="ECO:0000250" FT METAL 448 FT /note="Iron-sulfur (4Fe-4S)" FT /evidence="ECO:0000250" FT BINDING 95 FT /note="Substrate" FT /evidence="ECO:0000250" FT BINDING 471 FT /note="Substrate" FT /evidence="ECO:0000250" FT BINDING 476 FT /note="Substrate" FT /evidence="ECO:0000250" FT BINDING 604 FT /note="Substrate" FT /evidence="ECO:0000250" FT MOD_RES 391 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:19779198" FT MOD_RES 409 FT /note="Phosphothreonine" FT /evidence="ECO:0000244|PubMed:17761666" FT MOD_RES 556 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:17330950" FT MUTAGEN 604 FT /note="R->K: Strongly diminishes the catalytic activity FT towards both known substrates, aconitate and FT homoaconitate." FT /evidence="ECO:0000269|PubMed:23106124" FT CONFLICT 527..549 FT /note="DGLPQRGYDAGENTYQAPPADRS -> RWFASKEVMMLVRTLTKLHLQTVA FT (in Ref. 1; AAA34389)" FT /evidence="ECO:0000305" SQ SEQUENCE 778 AA; 85368 MW; AA9EB9A24388090E CRC64; MLSARSAIKR PIVRGLATVS NLTRDSKVNQ NLLEDHSFIN YKQNVETLDI VRKRLNRPFT YAEKILYGHL DDPHGQDIQR GVSYLKLRPD RVACQDATAQ MAILQFMSAG LPQVAKPVTV HCDHLIQAQV GGEKDLKRAI DLNKEVYDFL ASATAKYNMG FWKPGSGIIH QIVLENYAFP GALIIGTDSH TPNAGGLGQL AIGVGGADAV DVMAGRPWEL KAPKILGVKL TGKMNGWTSP KDIILKLAGI TTVKGGTGKI VEYFGDGVDT FSATGMGTIC NMGAEIGATT SVFPFNKSMI EYLEATGRGK IADFAKLYHK DLLSADKDAE YDEVVEIDLN TLEPYINGPF TPDLATPVSK MKEVAVANNW PLDVRVGLIG SCTNSSYEDM SRSASIVKDA AAHGLKSKTI FTVTPGSEQI RATIERDGQL ETFKEFGGIV LANACGPCIG QWDRRDIKKG DKNTIVSSYN RNFTSRNDGN PQTHAFVASP ELVTAFAIAG DLRFNPLTDK LKDKDGNEFM LKPPHGDGLP QRGYDAGENT YQAPPADRST VEVKVSPTSD RLQLLKPFKP WDGKDAKDMP ILIKAVGKTT TDHISMAGPW LKYRGHLENI SNNYMIGAIN AENKKANCVK NVYTGEYKGV PDTARDYRDQ GIKWVVIGDE NFGEGSSREH AALEPRFLGG FAIITKSFAR IHETNLKKQG LLPLNFKNPA DYDKINPDDR IDILGLAELA PGKPVTMRVH PKNGKPWDAV LTHTFNDEQI EWFKYGSALN KIKADEKK //