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Protein

Isocitrate lyase

Gene

icl

Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in the persistence and virulence of M.tuberculosis. Catalyzes the reversible formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle, which operates as an anaplerotic route for replenishing the tricarboxylic acid cycle during growth on fatty acid substrates (PubMed:10932251, PubMed:10963599, PubMed:18275086, PubMed:24354272). It could also catalyze the formation of pyruvate and succinate from 2-methylisocitrate, a key step in the methylcitrate cycle (propionate degradation route) (By similarity).By similarity4 Publications

Catalytic activityi

Isocitrate = succinate + glyoxylate.1 Publication

Cofactori

Mg2+2 PublicationsNote: Can also use Mn2+ ion.1 Publication

Enzyme regulationi

Inhibited by 3-nitropropionate (3-NP) and 3-bromopyruvate when M.tuberculosis grows on acetate, but not on glucose. Inhibition of ICL by 3-bromopyruvate is accomplished via dehalogenation of the inhibitor to form a covalent adduct with the active site Cys-191. Also inhibited by zinc and calcium ions.3 Publications

Kineticsi

Kcat is 12.2 sec(-1) for isocitrate lyase activity with isocitrate as substrate(at pH 7 and 37 degrees Celsius). Kcat is 8.5 sec(-1) for isocitrate lyase activity with succinate as substrate(at pH 7 and 37 degrees Celsius).1 Publication

Manual assertion based on experiment ini

  1. KM=45 µM for isocitrate (at pH 7 and 37 degrees Celsius)1 Publication
  2. KM=140 µM for glyoxylate (at pH 7 and 37 degrees Celsius)1 Publication
  3. KM=412 µM for succinate (at pH 7 and 37 degrees Celsius)1 Publication

    Pathwayi: glyoxylate cycle

    This protein is involved in step 1 of the subpathway that synthesizes (S)-malate from isocitrate.1 Publication
    Proteins known to be involved in the 2 steps of the subpathway in this organism are:
    1. Isocitrate lyase (icl)
    2. Malate synthase G (glcB), Malate synthase G (glcB)
    This subpathway is part of the pathway glyoxylate cycle, which is itself part of Carbohydrate metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes (S)-malate from isocitrate, the pathway glyoxylate cycle and in Carbohydrate metabolism.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi153Magnesium1 Publication1
    Active sitei191Proton acceptor1 Publication1
    Binding sitei228Substrate1 Publication1
    Binding sitei347Substrate1 Publication1

    GO - Molecular functioni

    GO - Biological processi

    • cellular response to hypoxia Source: MTBBASE
    • glyoxylate cycle Source: MTBBASE
    • isocitrate metabolic process Source: MTBBASE
    • maintenance of symbiont tolerance to host environment Source: MTBBASE
    • pathogenesis Source: MTBBASE
    • response to acetate Source: MTBBASE
    • response to acid chemical Source: MTBBASE
    • response to fatty acid Source: MTBBASE
    • response to host immune response Source: MTBBASE
    • tricarboxylic acid cycle Source: UniProtKB-KW
    Complete GO annotation...

    Keywords - Molecular functioni

    Lyase

    Keywords - Biological processi

    Glyoxylate bypass, Tricarboxylic acid cycle

    Keywords - Ligandi

    Magnesium, Manganese, Metal-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:G185E-4594-MONOMER.
    MTBH37RV:G185E-4594-MONOMER.
    UniPathwayiUPA00703; UER00719.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Isocitrate lyase1 Publication (EC:4.1.3.11 Publication)
    Short name:
    ICL1 Publication
    Alternative name(s):
    Isocitrase1 Publication
    Isocitratase1 Publication
    Gene namesi
    Name:icl
    Ordered Locus Names:Rv0467
    ORF Names:MTV038.11
    OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
    Taxonomic identifieri83332 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
    Proteomesi
    • UP000001584 Componenti: Chromosome

    Organism-specific databases

    TubercuListiRv0467.

    Subcellular locationi

    GO - Cellular componenti

    • cytosol Source: MTBBASE
    • plasma membrane Source: MTBBASE
    Complete GO annotation...

    Pathology & Biotechi

    Disruption phenotypei

    Cells lacking this gene show an attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi191C → S: Adopts a conformation almost identical to the wild-type. 1 Publication1

    Chemistry databases

    ChEMBLiCHEMBL1667699.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000687791 – 428Isocitrate lyaseAdd BLAST428

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Cross-linki334Isoglutamyl lysine isopeptide (Lys-Gln) (interchain with Q-Cter in protein Pup)1 Publication

    Post-translational modificationi

    Pupylated at Lys-334 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome.1 Publication

    Keywords - PTMi

    Isopeptide bond, Ubl conjugation

    Proteomic databases

    PaxDbiP9WKK7.

    Expressioni

    Inductioni

    Activated by PrpR and repressed by RamB.2 Publications

    Interactioni

    Subunit structurei

    Homotetramer.1 Publication

    Protein-protein interaction databases

    STRINGi83332.Rv0467.

    Chemistry databases

    BindingDBiP9WKK7.

    Structurei

    Secondary structure

    1428
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi10 – 19Combined sources10
    Helixi21 – 23Combined sources3
    Helixi32 – 38Combined sources7
    Helixi47 – 62Combined sources16
    Beta strandi66 – 70Combined sources5
    Helixi74 – 82Combined sources9
    Beta strandi88 – 90Combined sources3
    Helixi92 – 98Combined sources7
    Beta strandi108 – 110Combined sources3
    Helixi116 – 138Combined sources23
    Beta strandi150 – 153Combined sources4
    Turni155 – 158Combined sources4
    Helixi161 – 173Combined sources13
    Beta strandi177 – 182Combined sources6
    Helixi186 – 188Combined sources3
    Helixi202 – 218Combined sources17
    Beta strandi224 – 229Combined sources6
    Turni231 – 233Combined sources3
    Beta strandi236 – 238Combined sources3
    Turni243 – 245Combined sources3
    Helixi246 – 248Combined sources3
    Beta strandi249 – 253Combined sources5
    Beta strandi259 – 261Combined sources3
    Helixi265 – 275Combined sources11
    Helixi276 – 278Combined sources3
    Beta strandi280 – 284Combined sources5
    Helixi291 – 302Combined sources12
    Beta strandi309 – 313Combined sources5
    Beta strandi316 – 318Combined sources3
    Helixi320 – 323Combined sources4
    Helixi326 – 338Combined sources13
    Beta strandi341 – 346Combined sources6
    Helixi349 – 368Combined sources20
    Helixi370 – 383Combined sources14
    Helixi384 – 386Combined sources3
    Helixi393 – 396Combined sources4
    Helixi399 – 409Combined sources11
    Helixi422 – 426Combined sources5

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1F61X-ray2.00A/B2-428[»]
    1F8IX-ray2.25A/B/C/D2-428[»]
    1F8MX-ray1.80A/B/C/D2-428[»]
    5DQLX-ray1.78A/B/C/D1-428[»]
    ProteinModelPortaliP9WKK7.
    SMRiP9WKK7.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni91 – 93Substrate binding1 Publication3
    Regioni192 – 193Substrate binding1 Publication2
    Regioni313 – 317Substrate binding1 Publication5

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiENOG4107RPH. Bacteria.
    COG2224. LUCA.
    KOiK01637.
    OMAiLEKDWAE.
    PhylomeDBiP9WKK7.

    Family and domain databases

    Gene3Di3.20.20.60. 1 hit.
    InterProiIPR006254. Isocitrate_lyase.
    IPR018523. Isocitrate_lyase_ph_CS.
    IPR015813. Pyrv/PenolPyrv_Kinase-like_dom.
    [Graphical view]
    PfamiPF00463. ICL. 2 hits.
    [Graphical view]
    SUPFAMiSSF51621. SSF51621. 1 hit.
    TIGRFAMsiTIGR01346. isocit_lyase. 2 hits.
    PROSITEiPS00161. ISOCITRATE_LYASE. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P9WKK7-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSVVGTPKSA EQIQQEWDTN PRWKDVTRTY SAEDVVALQG SVVEEHTLAR
    60 70 80 90 100
    RGAEVLWEQL HDLEWVNALG ALTGNMAVQQ VRAGLKAIYL SGWQVAGDAN
    110 120 130 140 150
    LSGHTYPDQS LYPANSVPQV VRRINNALQR ADQIAKIEGD TSVENWLAPI
    160 170 180 190 200
    VADGEAGFGG ALNVYELQKA LIAAGVAGSH WEDQLASEKK CGHLGGKVLI
    210 220 230 240 250
    PTQQHIRTLT SARLAADVAD VPTVVIARTD AEAATLITSD VDERDQPFIT
    260 270 280 290 300
    GERTREGFYR TKNGIEPCIA RAKAYAPFAD LIWMETGTPD LEAARQFSEA
    310 320 330 340 350
    VKAEYPDQML AYNCSPSFNW KKHLDDATIA KFQKELAAMG FKFQFITLAG
    360 370 380 390 400
    FHALNYSMFD LAYGYAQNQM SAYVELQERE FAAEERGYTA TKHQREVGAG
    410 420
    YFDRIATTVD PNSSTTALTG STEEGQFH
    Length:428
    Mass (Da):47,087
    Last modified:April 16, 2014 - v1
    Checksum:iE5223F38CB5D9E8B
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP43200.1.
    PIRiG70828.
    RefSeqiWP_003402316.1. NZ_KK339370.1.
    YP_177728.1. NC_000962.3.

    Genome annotation databases

    EnsemblBacteriaiCCP43200; CCP43200; Rv0467.
    GeneIDi886291.
    KEGGimtu:Rv0467.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP43200.1.
    PIRiG70828.
    RefSeqiWP_003402316.1. NZ_KK339370.1.
    YP_177728.1. NC_000962.3.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1F61X-ray2.00A/B2-428[»]
    1F8IX-ray2.25A/B/C/D2-428[»]
    1F8MX-ray1.80A/B/C/D2-428[»]
    5DQLX-ray1.78A/B/C/D1-428[»]
    ProteinModelPortaliP9WKK7.
    SMRiP9WKK7.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi83332.Rv0467.

    Chemistry databases

    BindingDBiP9WKK7.
    ChEMBLiCHEMBL1667699.

    Proteomic databases

    PaxDbiP9WKK7.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiCCP43200; CCP43200; Rv0467.
    GeneIDi886291.
    KEGGimtu:Rv0467.

    Organism-specific databases

    TubercuListiRv0467.

    Phylogenomic databases

    eggNOGiENOG4107RPH. Bacteria.
    COG2224. LUCA.
    KOiK01637.
    OMAiLEKDWAE.
    PhylomeDBiP9WKK7.

    Enzyme and pathway databases

    UniPathwayiUPA00703; UER00719.
    BioCyciMetaCyc:G185E-4594-MONOMER.
    MTBH37RV:G185E-4594-MONOMER.

    Family and domain databases

    Gene3Di3.20.20.60. 1 hit.
    InterProiIPR006254. Isocitrate_lyase.
    IPR018523. Isocitrate_lyase_ph_CS.
    IPR015813. Pyrv/PenolPyrv_Kinase-like_dom.
    [Graphical view]
    PfamiPF00463. ICL. 2 hits.
    [Graphical view]
    SUPFAMiSSF51621. SSF51621. 1 hit.
    TIGRFAMsiTIGR01346. isocit_lyase. 2 hits.
    PROSITEiPS00161. ISOCITRATE_LYASE. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiACEA_MYCTU
    AccessioniPrimary (citable) accession number: P9WKK7
    Secondary accession number(s): L0T3N9, O53752, P0A5H3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 16, 2014
    Last sequence update: April 16, 2014
    Last modified: November 2, 2016
    This is version 18 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Was identified as a natural substrate of the M.tuberculosis proteasome.1 Publication

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh
      Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh: entries and gene names
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. 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.