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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.4 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

  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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi153 – 1531Magnesium1 Publication
Active sitei191 – 1911Proton acceptor1 Publication
Binding sitei228 – 2281Substrate1 Publication
Binding sitei347 – 3471Substrate1 Publication

GO - Molecular functioni

  1. isocitrate lyase activity Source: MTBBASE
  2. metal ion binding Source: UniProtKB-KW
  3. methylisocitrate lyase activity Source: MTBBASE

GO - Biological processi

  1. cellular response to hypoxia Source: MTBBASE
  2. glyoxylate cycle Source: MTBBASE
  3. isocitrate metabolic process Source: MTBBASE
  4. maintenance of symbiont tolerance to host environment Source: MTBBASE
  5. pathogenesis Source: MTBBASE
  6. response to acetate Source: MTBBASE
  7. response to acid chemical Source: MTBBASE
  8. response to fatty acid Source: MTBBASE
  9. response to host immune response Source: MTBBASE
  10. 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

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
Isocitratsysase1 Publication
Gene namesi
Name:icl
Ordered Locus Names:Rv0467
ORF Names:MTV038.11
OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Taxonomic identifieri83332 [NCBI]
Taxonomic lineageiBacteriaActinobacteriaActinobacteridaeActinomycetalesCorynebacterineaeMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
ProteomesiUP000001584 Componenti: Chromosome

Organism-specific databases

TubercuListiRv0467.

Subcellular locationi

GO - Cellular componenti

  1. cytosol Source: MTBBASE
  2. 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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi191 – 1911C → S: Adopts a conformation almost identical to the wild-type. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 428428Isocitrate lyasePRO_0000068779Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki334 – 334Isoglutamyl 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

Interactioni

Subunit structurei

Homotetramer.1 Publication

Structurei

Secondary structure

1
428
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi10 – 1910
Helixi21 – 233
Helixi32 – 387
Helixi47 – 6216
Beta strandi66 – 705
Helixi74 – 829
Beta strandi88 – 903
Helixi92 – 987
Beta strandi108 – 1103
Helixi116 – 13823
Beta strandi150 – 1534
Turni155 – 1584
Helixi161 – 17313
Beta strandi177 – 1826
Helixi186 – 1883
Helixi202 – 21817
Beta strandi224 – 2296
Turni231 – 2333
Beta strandi236 – 2383
Turni243 – 2453
Helixi246 – 2483
Beta strandi249 – 2535
Beta strandi259 – 2613
Helixi265 – 27511
Helixi276 – 2783
Beta strandi280 – 2845
Helixi291 – 30212
Beta strandi309 – 3135
Beta strandi316 – 3183
Helixi320 – 3234
Helixi326 – 33813
Beta strandi341 – 3466
Helixi349 – 36820
Helixi370 – 38314
Helixi384 – 3863
Helixi393 – 3964
Helixi399 – 40911
Helixi422 – 4265

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1F61X-ray2.00A/B2-428[»]
1F8IX-ray2.25A/B/C/D2-428[»]
1F8MX-ray1.80A/B/C/D2-428[»]
ProteinModelPortaliP9WKK7.
SMRiP9WKK7. Positions 2-427.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni91 – 933Substrate binding1 Publication
Regioni192 – 1932Substrate binding1 Publication
Regioni313 – 3175Substrate binding1 Publication

Sequence similaritiesi

Phylogenomic databases

KOiK01637.
OMAiRWKGVTR.
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]
PANTHERiPTHR21631:SF3. PTHR21631:SF3. 1 hit.
PfamiPF00463. ICL. 1 hit.
[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.
RefSeqiYP_006513796.1. NC_018143.2.
YP_177728.1. NC_000962.3.

Genome annotation databases

EnsemblBacteriaiCCP43200; CCP43200; Rv0467.
GeneIDi886291.
KEGGimtu:Rv0467.
mtv:RVBD_0467.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL123456 Genomic DNA. Translation: CCP43200.1.
PIRiG70828.
RefSeqiYP_006513796.1. NC_018143.2.
YP_177728.1. NC_000962.3.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1F61X-ray2.00A/B2-428[»]
1F8IX-ray2.25A/B/C/D2-428[»]
1F8MX-ray1.80A/B/C/D2-428[»]
ProteinModelPortaliP9WKK7.
SMRiP9WKK7. Positions 2-427.
ModBaseiSearch...
MobiDBiSearch...

Chemistry

BindingDBiP9WKK7.
ChEMBLiCHEMBL1667699.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiCCP43200; CCP43200; Rv0467.
GeneIDi886291.
KEGGimtu:Rv0467.
mtv:RVBD_0467.

Organism-specific databases

TubercuListiRv0467.

Phylogenomic databases

KOiK01637.
OMAiRWKGVTR.
PhylomeDBiP9WKK7.

Enzyme and pathway databases

UniPathwayiUPA00703; UER00719.

Miscellaneous databases

PROiP9WKK7.

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]
PANTHERiPTHR21631:SF3. PTHR21631:SF3. 1 hit.
PfamiPF00463. ICL. 1 hit.
[Graphical view]
SUPFAMiSSF51621. SSF51621. 1 hit.
TIGRFAMsiTIGR01346. isocit_lyase. 2 hits.
PROSITEiPS00161. ISOCITRATE_LYASE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: ATCC 25618 / H37Rv.
  2. "Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase."
    McKinney J.D., Honer zu Bentrup K., Munoz-Elias E.J., Miczak A., Chen B., Chan W.T., Swenson D., Sacchettini J.C., Jacobs W.R. Jr., Russell D.G.
    Nature 406:735-738(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  3. "Mycobacterium tuberculosis isocitrate lyase (MtbIcl): role of divalent cations in modulation of functional and structural properties."
    Kumar R., Bhakuni V.
    Proteins 72:892-900(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, COFACTOR, ENZYME REGULATION.
  4. "Prokayrotic ubiquitin-like protein (Pup) proteome of Mycobacterium tuberculosis."
    Festa R.A., McAllister F., Pearce M.J., Mintseris J., Burns K.E., Gygi S.P., Darwin K.H.
    PLoS ONE 5:E8589-E8589(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEASOME SUBSTRATE, PUPYLATION AT LYS-334, IDENTIFICATION BY MASS SPECTROMETRY.
    Strain: ATCC 25618 / H37Rv.
  5. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Strain: ATCC 25618 / H37Rv.
  6. "Cysteine is the general base that serves in catalysis by isocitrate lyase and in mechanism-based inhibition by 3-nitropropionate."
    Moynihan M.M., Murkin A.S.
    Biochemistry 53:178-187(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, ACTIVE SITE.
  7. "Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis."
    Sharma V., Sharma S., zu Bentrup K.H., McKinney J.D., Russell D.G., Jacobs W.R. Jr., Sacchettini J.C.
    Nat. Struct. Biol. 7:663-668(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF WILD-TYPE AND MUTANT SER-191 IN COMPLEX WITH SUBSTRATES AND MAGNESIUM, FUNCTION, MUTAGENESIS OF CYS-191, ENZYME REGULATION, COFACTOR, SUBUNIT, REACTION MECHANISM.

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: April 29, 2015
This is version 11 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

External Data

Dasty 3

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 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.