ID   LYS12_YEAST             Reviewed;         371 AA.
AC   P40495; D6VVJ3;
DT   01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1995, sequence version 1.
DT   27-MAR-2024, entry version 187.
DE   RecName: Full=Homoisocitrate dehydrogenase, mitochondrial;
DE            Short=HIcDH;
DE            EC=1.1.1.87;
DE   Flags: Precursor;
GN   Name=LYS12; Synonyms=LYS10, LYS11; OrderedLocusNames=YIL094C;
GN   ORFNames=YI9910.02C;
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 [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169870;
RA   Churcher C.M., Bowman S., Badcock K., Bankier A.T., Brown D.,
RA   Chillingworth T., Connor R., Devlin K., Gentles S., Hamlin N., Harris D.E.,
RA   Horsnell T., Hunt S., Jagels K., Jones M., Lye G., Moule S., Odell C.,
RA   Pearson D., Rajandream M.A., Rice P., Rowley N., Skelton J., Smith V.,
RA   Walsh S.V., Whitehead S., Barrell B.G.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome IX.";
RL   Nature 387:84-87(1997).
RN   [2]
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   [3]
RP   PROTEIN SEQUENCE OF 23-36; 103-114; 116-127; 181-192; 237-248; 309-318 AND
RP   346-370, AND IDENTIFICATION BY MASS SPECTROMETRY.
RA   Bienvenut W.V., Peters C.;
RL   Submitted (JUN-2005) to UniProtKB.
RN   [4]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=4284830; DOI=10.1016/s0021-9258(18)97069-9;
RA   Strassman M., Ceci L.N.;
RT   "Enzymatic formation of alpha-ketoadipic acid from homoisocitric acid.";
RL   J. Biol. Chem. 240:4357-4361(1965).
RN   [5]
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=4395693; DOI=10.1016/0003-9861(70)90167-0;
RA   Rowley B., Tucci A.F.;
RT   "Homoisocitric dehydrogenase from yeast.";
RL   Arch. Biochem. Biophys. 141:499-510(1970).
RN   [6]
RP   INDUCTION.
RX   PubMed=3939712; DOI=10.1007/bf00421603;
RA   Urrestarazu L.A., Borell C.W., Bhattacharjee J.K.;
RT   "General and specific controls of lysine biosynthesis in Saccharomyces
RT   cerevisiae.";
RL   Curr. Genet. 9:341-344(1985).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=8962070; DOI=10.1073/pnas.93.25.14440;
RA   Shevchenko A., Jensen O.N., Podtelejnikov A.V., Sagliocco F., Wilm M.,
RA   Vorm O., Mortensen P., Shevchenko A., Boucherie H., Mann M.;
RT   "Linking genome and proteome by mass spectrometry: large-scale
RT   identification of yeast proteins from two dimensional gels.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:14440-14445(1996).
RN   [8]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX   PubMed=14562095; DOI=10.1038/nature02026;
RA   Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W.,
RA   Weissman J.S., O'Shea E.K.;
RT   "Global analysis of protein localization in budding yeast.";
RL   Nature 425:686-691(2003).
RN   [9]
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   [10]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RC   STRAIN=ATCC 76625 / YPH499;
RX   PubMed=14576278; DOI=10.1073/pnas.2135385100;
RA   Sickmann A., Reinders J., Wagner Y., Joppich C., Zahedi R.P., Meyer H.E.,
RA   Schoenfisch B., Perschil I., Chacinska A., Guiard B., Rehling P.,
RA   Pfanner N., Meisinger C.;
RT   "The proteome of Saccharomyces cerevisiae mitochondria.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:13207-13212(2003).
RN   [11]
RP   CATALYTIC ACTIVITY, COFACTOR, AND ACTIVITY REGULATION.
RX   PubMed=17223711; DOI=10.1021/bi062067q;
RA   Lin Y., Alguindigue S.S., Volkman J., Nicholas K.M., West A.H., Cook P.F.;
RT   "Complete kinetic mechanism of homoisocitrate dehydrogenase from
RT   Saccharomyces cerevisiae.";
RL   Biochemistry 46:890-898(2007).
RN   [12]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-98, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=18407956; DOI=10.1074/mcp.m700468-mcp200;
RA   Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.;
RT   "A multidimensional chromatography technology for in-depth phosphoproteome
RT   analysis.";
RL   Mol. Cell. Proteomics 7:1389-1396(2008).
RN   [13]
RP   CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF TYR-150 AND LYS-206.
RX   PubMed=19530703; DOI=10.1021/bi900175z;
RA   Lin Y., West A.H., Cook P.F.;
RT   "Site-directed mutagenesis as a probe of the acid-base catalytic mechanism
RT   of homoisocitrate dehydrogenase from Saccharomyces cerevisiae.";
RL   Biochemistry 48:7305-7312(2009).
CC   -!- FUNCTION: Catalyzes the NAD(+)-dependent conversion of homoisocitrate
CC       to alpha-ketoadipate. {ECO:0000269|PubMed:4284830}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(2R,3S)-homoisocitrate + NAD(+) = 2-oxoadipate + CO2 + NADH;
CC         Xref=Rhea:RHEA:11900, ChEBI:CHEBI:15404, ChEBI:CHEBI:16526,
CC         ChEBI:CHEBI:57499, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.87;
CC         Evidence={ECO:0000269|PubMed:17223711, ECO:0000269|PubMed:19530703,
CC         ECO:0000269|PubMed:4284830};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:17223711, ECO:0000269|PubMed:19530703};
CC       Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000269|PubMed:17223711,
CC       ECO:0000269|PubMed:19530703};
CC   -!- ACTIVITY REGULATION: Inhibited by the reaction product NADH. Inhibited
CC       by oxalate; this is a non-competitive inhibitor.
CC       {ECO:0000269|PubMed:17223711}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=1.5 mM for 2-oxoadipate {ECO:0000269|PubMed:4395693};
CC         KM=330 uM for NAD(+) {ECO:0000269|PubMed:4395693};
CC         KM=65 uM for NADH {ECO:0000269|PubMed:4395693};
CC         Note=The KM for homoisocitrate is lower than 10 uM.;
CC       pH dependence:
CC         Optimum pH is 8.3-8.8 for the forward reaction, and 7 for the reverse
CC         reaction. {ECO:0000269|PubMed:4395693};
CC   -!- PATHWAY: Amino-acid biosynthesis; L-lysine biosynthesis via AAA
CC       pathway; L-alpha-aminoadipate from 2-oxoglutarate: step 4/5.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095,
CC       ECO:0000269|PubMed:14576278}.
CC   -!- INDUCTION: Activity is repressed 4-fold by lysine.
CC       {ECO:0000269|PubMed:3939712}.
CC   -!- MISCELLANEOUS: Present with 19079 molecules/cell in log phase SD
CC       medium. {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC       dehydrogenases family. {ECO:0000305}.
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DR   EMBL; Z46728; CAA86700.1; -; Genomic_DNA.
DR   EMBL; BK006942; DAA08459.1; -; Genomic_DNA.
DR   PIR; S49786; S49786.
DR   RefSeq; NP_012172.1; NM_001179442.1.
DR   AlphaFoldDB; P40495; -.
DR   SMR; P40495; -.
DR   BioGRID; 34898; 126.
DR   DIP; DIP-4162N; -.
DR   IntAct; P40495; 101.
DR   MINT; P40495; -.
DR   STRING; 4932.YIL094C; -.
DR   BindingDB; P40495; -.
DR   ChEMBL; CHEMBL1075252; -.
DR   iPTMnet; P40495; -.
DR   MaxQB; P40495; -.
DR   PaxDb; 4932-YIL094C; -.
DR   PeptideAtlas; P40495; -.
DR   EnsemblFungi; YIL094C_mRNA; YIL094C; YIL094C.
DR   GeneID; 854714; -.
DR   KEGG; sce:YIL094C; -.
DR   AGR; SGD:S000001356; -.
DR   SGD; S000001356; LYS12.
DR   VEuPathDB; FungiDB:YIL094C; -.
DR   eggNOG; KOG0785; Eukaryota.
DR   GeneTree; ENSGT00950000182989; -.
DR   HOGENOM; CLU_031953_0_1_1; -.
DR   InParanoid; P40495; -.
DR   OMA; DSFVMGE; -.
DR   OrthoDB; 143577at2759; -.
DR   BioCyc; YEAST:YIL094C-MONOMER; -.
DR   BRENDA; 1.1.1.87; 984.
DR   UniPathway; UPA00033; UER00030.
DR   BioGRID-ORCS; 854714; 2 hits in 10 CRISPR screens.
DR   ChiTaRS; LYS12; yeast.
DR   PRO; PR:P40495; -.
DR   Proteomes; UP000002311; Chromosome IX.
DR   RNAct; P40495; Protein.
DR   GO; GO:0005739; C:mitochondrion; HDA:SGD.
DR   GO; GO:0047046; F:homoisocitrate dehydrogenase activity; IDA:SGD.
DR   GO; GO:0004449; F:isocitrate dehydrogenase (NAD+) activity; IBA:GO_Central.
DR   GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR   GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR   GO; GO:0006102; P:isocitrate metabolic process; IBA:GO_Central.
DR   GO; GO:0009085; P:lysine biosynthetic process; IBA:GO_Central.
DR   GO; GO:0019878; P:lysine biosynthetic process via aminoadipic acid; IEA:UniProtKB-UniPathway.
DR   GO; GO:0006099; P:tricarboxylic acid cycle; IBA:GO_Central.
DR   Gene3D; 3.40.718.10; Isopropylmalate Dehydrogenase; 1.
DR   InterPro; IPR019818; IsoCit/isopropylmalate_DH_CS.
DR   InterPro; IPR024084; IsoPropMal-DH-like_dom.
DR   PANTHER; PTHR11835; DECARBOXYLATING DEHYDROGENASES-ISOCITRATE, ISOPROPYLMALATE, TARTRATE; 1.
DR   PANTHER; PTHR11835:SF48; HOMOISOCITRATE DEHYDROGENASE, MITOCHONDRIAL; 1.
DR   Pfam; PF00180; Iso_dh; 1.
DR   SMART; SM01329; Iso_dh; 1.
DR   SUPFAM; SSF53659; Isocitrate/Isopropylmalate dehydrogenase-like; 1.
DR   PROSITE; PS00470; IDH_IMDH; 1.
PE   1: Evidence at protein level;
KW   Amino-acid biosynthesis; Direct protein sequencing; Lysine biosynthesis;
KW   Magnesium; Metal-binding; Mitochondrion; NAD; Oxidoreductase;
KW   Phosphoprotein; Reference proteome; Transit peptide.
FT   TRANSIT         1..22
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           23..371
FT                   /note="Homoisocitrate dehydrogenase, mitochondrial"
FT                   /id="PRO_0000043097"
FT   BINDING         96..98
FT                   /ligand="NADH"
FT                   /ligand_id="ChEBI:CHEBI:57945"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         98
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         114
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         124
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         143
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         150
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /note="in other chain"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         206
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         208
FT                   /ligand="(2R,3S)-homoisocitrate"
FT                   /ligand_id="ChEBI:CHEBI:15404"
FT                   /ligand_note="ligand shared between homodimeric partners"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         208
FT                   /ligand="NADH"
FT                   /ligand_id="ChEBI:CHEBI:57945"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         243
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         267
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         271
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         300..304
FT                   /ligand="NADH"
FT                   /ligand_id="ChEBI:CHEBI:57945"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   BINDING         312
FT                   /ligand="NADH"
FT                   /ligand_id="ChEBI:CHEBI:57945"
FT                   /evidence="ECO:0000250|UniProtKB:Q72IW9"
FT   SITE            150
FT                   /note="Critical for catalysis"
FT   SITE            206
FT                   /note="Critical for catalysis"
FT   MOD_RES         98
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956"
FT   MUTAGEN         150
FT                   /note="Y->F: Strongly reduced enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:19530703"
FT   MUTAGEN         206
FT                   /note="K->M: Strongly reduced enzyme activity."
FT                   /evidence="ECO:0000269|PubMed:19530703"
SQ   SEQUENCE   371 AA;  40069 MW;  43CAFA86F75ED3C6 CRC64;
     MFRSVATRLS ACRGLASNAA RKSLTIGLIP GDGIGKEVIP AGKQVLENLN SKHGLSFNFI
     DLYAGFQTFQ ETGKALPDET VKVLKEQCQG ALFGAVQSPT TKVEGYSSPI VALRREMGLF
     ANVRPVKSVE GEKGKPIDMV IVRENTEDLY IKIEKTYIDK ATGTRVADAT KRISEIATRR
     IATIALDIAL KRLQTRGQAT LTVTHKSNVL SQSDGLFREI CKEVYESNKD KYGQIKYNEQ
     IVDSMVYRLF REPQCFDVIV APNLYGDILS DGAAALVGSL GVVPSANVGP EIVIGEPCHG
     SAPDIAGKGI ANPIATIRST ALMLEFLGHN EAAQDIYKAV DANLREGSIK TPDLGGKAST
     QQVVDDVLSR L
//