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Protein

Homoisocitrate dehydrogenase

Gene

hicd

Organism
Thermus thermophilus (strain HB27 / ATCC BAA-163 / DSM 7039)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the NAD+-dependent conversion of homoisocitrate to alpha-ketoadipate. In addition, has high activity with citrate, but is inactive with 3-isopropylmalate.2 Publications

Catalytic activityi

(1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate + NAD+ = 2-oxoadipate + CO2 + NADH.3 Publications

Cofactori

Mg2+By similarity, Mn2+By similarityNote: Binds 1 Mg2+ or Mn2+ ion per subunit.By similarity

Kineticsi

  1. KM=7486 µM for homoisocitrate1 Publication
  2. KM=405 µM for isocitrate1 Publication

    Pathwayi: L-lysine biosynthesis via AAA pathway

    This protein is involved in step 4 of the subpathway that synthesizes L-alpha-aminoadipate from 2-oxoglutarate.1 Publication
    Proteins known to be involved in the 5 steps of the subpathway in this organism are:
    1. Homocitrate synthase (lys20)
    2. no protein annotated in this organism
    3. Homoaconitase large subunit (hacA), Homoaconitase small subunit (hacB)
    4. Homoisocitrate dehydrogenase (hicd)
    5. 2-aminoadipate transaminase (lysN)
    This subpathway is part of the pathway L-lysine biosynthesis via AAA pathway, which is itself part of Amino-acid biosynthesis.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes L-alpha-aminoadipate from 2-oxoglutarate, the pathway L-lysine biosynthesis via AAA pathway and in Amino-acid biosynthesis.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei85 – 851Important for substrate specificity and discrimination against 3-isopropylmalate
    Binding sitei88 – 881SubstrateBy similarity
    Binding sitei98 – 981SubstrateBy similarity
    Binding sitei118 – 1181SubstrateBy similarity
    Sitei125 – 1251Critical for catalysisBy similarity
    Sitei171 – 1711Critical for catalysisBy similarity
    Metal bindingi204 – 2041Magnesium or manganeseBy similarity
    Binding sitei204 – 2041SubstrateBy similarity
    Metal bindingi228 – 2281Magnesium or manganeseBy similarity
    Metal bindingi232 – 2321Magnesium or manganeseBy similarity

    GO - Molecular functioni

    • homoisocitrate dehydrogenase activity Source: UniProtKB
    • magnesium ion binding Source: InterPro
    • NAD binding Source: InterPro

    GO - Biological processi

    • lysine biosynthetic process via aminoadipic acid Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    Amino-acid biosynthesis, Lysine biosynthesis

    Keywords - Ligandi

    Magnesium, Manganese, Metal-binding, NAD

    Enzyme and pathway databases

    BioCyciTTHE262724:GCAT-1024-MONOMER.
    BRENDAi1.1.1.85. 2305.
    UniPathwayiUPA00033; UER00030.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Homoisocitrate dehydrogenase (EC:1.1.1.87)
    Short name:
    HICDH
    Gene namesi
    Name:hicd
    Synonyms:hdh, hicdh
    Ordered Locus Names:TT_C1012
    OrganismiThermus thermophilus (strain HB27 / ATCC BAA-163 / DSM 7039)
    Taxonomic identifieri262724 [NCBI]
    Taxonomic lineageiBacteriaDeinococcus-ThermusDeinococciThermalesThermaceaeThermus
    Proteomesi
    • UP000000592 Componenti: Chromosome

    Pathology & Biotechi

    Disruption phenotypei

    Does not grow on minimal medium. Requires alpha-aminoadipate or lysine for growth.1 Publication

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi57 – 571E → V: Confers enzyme activity with 3-isopropylmalate; when associated with I-72; M-85; A-86; T-208; Y-217; M-238 and M-310. 1 Publication
    Mutagenesisi72 – 721S → I: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; M-85; A-86; T-208; Y-217; M-238 and M-310. 1 Publication
    Mutagenesisi78 – 869PGFFGAIRY → EGYSSPIVA: Reduces activity with homoisocitrate. Abolishes activity with isocitrate. No activity with 3-isopropylmalate.
    Mutagenesisi78 – 836PGFFGA → EGYSSP: Reduces activity with homoisocitrate. Reduces activity with isocitrate. No activity with 3-isopropylmalate.
    Mutagenesisi80 – 834FFGA → YSSP: Strongly reduces activity with homoisocitrate. Reduces activity with isocitrate. No activity with 3-isopropylmalate.
    Mutagenesisi85 – 851R → M: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; A-86; T-208; Y-217; M-238 and M-310. 2 Publications
    Mutagenesisi85 – 851R → V: Confers low enzyme activity with 3-isopropylmalate. Reduces activity with homoisocitrate. Abolishes activity with isocitrate. 2 Publications
    Mutagenesisi86 – 861Y → A: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; M-85; T-208; Y-217; M-238 and M-310. 1 Publication
    Mutagenesisi125 – 1251Y → A: Reduces catalytic efficiency with isocitrate. 1 Publication
    Mutagenesisi135 – 1351V → M: Formation of homodimers instead of homotetramers. Increased affinity for isocitrate. Reduces enzyme activity with isocitrate. 1 Publication
    Mutagenesisi208 – 2081M → T: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; M-85; A-86; T-208; Y-217; M-238 and M-310. 1 Publication
    Mutagenesisi217 – 2171F → Y: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; M-85; A-86; T-208; M-238 and M-310. 1 Publication
    Mutagenesisi238 – 2381V → M: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; M-85; A-86; T-208; Y-217; and M-310. 1 Publication
    Mutagenesisi310 – 3101R → M: Confers enzyme activity with 3-isopropylmalate; when associated with V-57; I-72; M-85; A-86; T-208; Y-217; and M-238. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 334334Homoisocitrate dehydrogenasePRO_0000422304Add
    BLAST

    Interactioni

    Subunit structurei

    Homotetramer. Dimer of dimers. The homotetramer can transiently dissociate into homodimers.2 Publications

    Protein-protein interaction databases

    STRINGi262724.TTC1012.

    Structurei

    Secondary structure

    1
    334
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi3 – 119Combined sources
    Helixi14 – 2613Combined sources
    Turni27 – 293Combined sources
    Beta strandi32 – 376Combined sources
    Helixi41 – 477Combined sources
    Beta strandi48 – 514Combined sources
    Helixi53 – 608Combined sources
    Beta strandi62 – 698Combined sources
    Beta strandi74 – 763Combined sources
    Helixi83 – 908Combined sources
    Beta strandi95 – 1017Combined sources
    Beta strandi113 – 1197Combined sources
    Helixi121 – 1233Combined sources
    Beta strandi129 – 1324Combined sources
    Beta strandi135 – 1439Combined sources
    Helixi144 – 15916Combined sources
    Beta strandi165 – 1706Combined sources
    Turni172 – 1743Combined sources
    Helixi178 – 19013Combined sources
    Beta strandi196 – 2027Combined sources
    Helixi203 – 21210Combined sources
    Helixi214 – 2163Combined sources
    Beta strandi218 – 2225Combined sources
    Helixi224 – 23714Combined sources
    Beta strandi245 – 2495Combined sources
    Beta strandi254 – 2607Combined sources
    Helixi264 – 2663Combined sources
    Helixi275 – 28814Combined sources
    Helixi291 – 30717Combined sources
    Helixi312 – 3143Combined sources
    Helixi320 – 33213Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1X0LX-ray1.85A/B2-334[»]
    3AH3X-ray2.40A/B/C/D1-334[»]
    4YB4X-ray2.50A/B/C/D1-334[»]
    ProteinModelPortaliQ72IW9.
    SMRiQ72IW9. Positions 2-334.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiENOG4105C0C. Bacteria.
    COG0473. LUCA.
    KOiK05824.
    OMAiQCCDEVA.
    OrthoDBiEOG65XN31.

    Family and domain databases

    Gene3Di3.40.718.10. 1 hit.
    InterProiIPR001804. Isocitrate/isopropylmalate_DH.
    IPR024084. IsoPropMal-DH-like_dom.
    [Graphical view]
    PANTHERiPTHR11835. PTHR11835. 1 hit.
    PfamiPF00180. Iso_dh. 1 hit.
    [Graphical view]
    SMARTiSM01329. Iso_dh. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q72IW9-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MAYRICLIEG DGIGHEVIPA ARRVLEATGL PLEFVEAEAG WETFERRGTS
    60 70 80 90 100
    VPEETVEKIL SCHATLFGAA TSPTRKVPGF FGAIRYLRRR LDLYANVRPA
    110 120 130 140 150
    KSRPVPGSRP GVDLVIVREN TEGLYVEQER RYLDVAIADA VISKKASERI
    160 170 180 190 200
    GRAALRIAEG RPRKTLHIAH KANVLPLTQG LFLDTVKEVA KDFPLVNVQD
    210 220 230 240 250
    IIVDNCAMQL VMRPERFDVI VTTNLLGDIL SDLAAGLVGG LGLAPSGNIG
    260 270 280 290 300
    DTTAVFEPVH GSAPDIAGKG IANPTAAILS AAMMLDYLGE KEAAKRVEKA
    310 320 330
    VDLVLERGPR TPDLGGDATT EAFTEAVVEA LKSL
    Length:334
    Mass (Da):35,922
    Last modified:July 5, 2004 - v1
    Checksum:i82B018FED744FB49
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AB075751 Genomic DNA. Translation: BAB88861.1.
    AE017221 Genomic DNA. Translation: AAS81354.1.
    RefSeqiWP_011173431.1. NC_005835.1.

    Genome annotation databases

    EnsemblBacteriaiAAS81354; AAS81354; TT_C1012.
    KEGGitth:TTC1012.
    PATRICi23952429. VBITheThe54392_1005.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AB075751 Genomic DNA. Translation: BAB88861.1.
    AE017221 Genomic DNA. Translation: AAS81354.1.
    RefSeqiWP_011173431.1. NC_005835.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1X0LX-ray1.85A/B2-334[»]
    3AH3X-ray2.40A/B/C/D1-334[»]
    4YB4X-ray2.50A/B/C/D1-334[»]
    ProteinModelPortaliQ72IW9.
    SMRiQ72IW9. Positions 2-334.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi262724.TTC1012.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiAAS81354; AAS81354; TT_C1012.
    KEGGitth:TTC1012.
    PATRICi23952429. VBITheThe54392_1005.

    Phylogenomic databases

    eggNOGiENOG4105C0C. Bacteria.
    COG0473. LUCA.
    KOiK05824.
    OMAiQCCDEVA.
    OrthoDBiEOG65XN31.

    Enzyme and pathway databases

    UniPathwayiUPA00033; UER00030.
    BioCyciTTHE262724:GCAT-1024-MONOMER.
    BRENDAi1.1.1.85. 2305.

    Family and domain databases

    Gene3Di3.40.718.10. 1 hit.
    InterProiIPR001804. Isocitrate/isopropylmalate_DH.
    IPR024084. IsoPropMal-DH-like_dom.
    [Graphical view]
    PANTHERiPTHR11835. PTHR11835. 1 hit.
    PfamiPF00180. Iso_dh. 1 hit.
    [Graphical view]
    SMARTiSM01329. Iso_dh. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "Characterization of homoisocitrate dehydrogenase involved in lysine biosynthesis of an extremely thermophilic bacterium, Thermus thermophilus HB27, and evolutionary implication of beta-decarboxylating dehydrogenase."
      Miyazaki J., Kobashi N., Nishiyama M., Yamane H.
      J. Biol. Chem. 278:1864-1871(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, DISRUPTION PHENOTYPE, PATHWAY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF ARG-85.
      Strain: HB27 / ATCC BAA-163 / DSM 7039.
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: HB27 / ATCC BAA-163 / DSM 7039.
    3. "Crystal structure of tetrameric homoisocitrate dehydrogenase from an extreme thermophile, Thermus thermophilus: involvement of hydrophobic dimer-dimer interaction in extremely high thermotolerance."
      Miyazaki J., Asada K., Fushinobu S., Kuzuyama T., Nishiyama M.
      J. Bacteriol. 187:6779-6788(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS), CATALYTIC ACTIVITY, MUTAGENESIS OF TYR-125 AND VAL-135, SUBUNIT.
      Strain: HB27 / ATCC BAA-163 / DSM 7039.
    4. "Enhancement of the latent 3-isopropylmalate dehydrogenase activity of promiscuous homoisocitrate dehydrogenase by directed evolution."
      Suzuki Y., Asada K., Miyazaki J., Tomita T., Kuzuyama T., Nishiyama M.
      Biochem. J. 431:401-410(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF MUTANT VAL-57/ILE-72/MET-85/ALA-86/THR-208/TYR-217/MET-238/MET-310, CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF GLU-57; SER-72; ARG-85; TYR-86; MET-208; PHE-217; VAL-238 AND ARG-310.
      Strain: HB27 / ATCC BAA-163 / DSM 7039.

    Entry informationi

    Entry nameiHICDH_THET2
    AccessioniPrimary (citable) accession number: Q72IW9
    Secondary accession number(s): Q8RQU4
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 29, 2013
    Last sequence update: July 5, 2004
    Last modified: May 11, 2016
    This is version 75 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    In vitro directed evolution leads to mutagenesis of key residues and increased activity with 3-isopropylmalate.

    Keywords - Technical termi

    3D-structure, Complete proteome

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.