ID   ACEA_MYCTU              Reviewed;         428 AA.
AC   P9WKK7; L0T3N9; O53752; P0A5H3;
DT   16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT   16-APR-2014, sequence version 1.
DT   27-MAR-2024, entry version 50.
DE   RecName: Full=Isocitrate lyase {ECO:0000303|PubMed:10963599};
DE            Short=ICL {ECO:0000303|PubMed:10963599};
DE            EC=4.1.3.1 {ECO:0000269|PubMed:24354272};
DE   AltName: Full=Isocitrase {ECO:0000303|PubMed:10963599};
DE   AltName: Full=Isocitratase {ECO:0000303|PubMed:10963599};
GN   Name=icl; OrderedLocusNames=Rv0467; ORFNames=MTV038.11;
OS   Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC   Bacteria; Actinomycetota; Actinomycetes; Mycobacteriales; Mycobacteriaceae;
OC   Mycobacterium; Mycobacterium tuberculosis complex.
OX   NCBI_TaxID=83332;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=9634230; DOI=10.1038/31159;
RA   Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA   Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA   Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA   Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA   Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA   Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA   Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA   Barrell B.G.;
RT   "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT   genome sequence.";
RL   Nature 393:537-544(1998).
RN   [2]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=10963599; DOI=10.1038/35021074;
RA   McKinney J.D., Honer zu Bentrup K., Munoz-Elias E.J., Miczak A., Chen B.,
RA   Chan W.T., Swenson D., Sacchettini J.C., Jacobs W.R. Jr., Russell D.G.;
RT   "Persistence of Mycobacterium tuberculosis in macrophages and mice requires
RT   the glyoxylate shunt enzyme isocitrate lyase.";
RL   Nature 406:735-738(2000).
RN   [3]
RP   FUNCTION, COFACTOR, AND ACTIVITY REGULATION.
RX   PubMed=18275086; DOI=10.1002/prot.21984;
RA   Kumar R., Bhakuni V.;
RT   "Mycobacterium tuberculosis isocitrate lyase (MtbIcl): role of divalent
RT   cations in modulation of functional and structural properties.";
RL   Proteins 72:892-900(2008).
RN   [4]
RP   PROTEASOME SUBSTRATE, PUPYLATION AT LYS-334, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=20066036; DOI=10.1371/journal.pone.0008589;
RA   Festa R.A., McAllister F., Pearce M.J., Mintseris J., Burns K.E.,
RA   Gygi S.P., Darwin K.H.;
RT   "Prokaryotic ubiquitin-like protein (Pup) proteome of Mycobacterium
RT   tuberculosis.";
RL   PLoS ONE 5:E8589-E8589(2010).
RN   [5]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=21969609; DOI=10.1074/mcp.m111.011445;
RA   Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA   Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA   Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA   Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT   "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT   mass spectrometry.";
RL   Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP   REGULATION, AND ACTIVE SITE.
RX   PubMed=24354272; DOI=10.1021/bi401432t;
RA   Moynihan M.M., Murkin A.S.;
RT   "Cysteine is the general base that serves in catalysis by isocitrate lyase
RT   and in mechanism-based inhibition by 3-nitropropionate.";
RL   Biochemistry 53:178-187(2014).
RN   [7]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF WILD-TYPE AND MUTANT SER-191 IN
RP   COMPLEX WITH SUBSTRATES AND MAGNESIUM, FUNCTION, MUTAGENESIS OF CYS-191,
RP   ACTIVITY REGULATION, COFACTOR, SUBUNIT, AND REACTION MECHANISM.
RX   PubMed=10932251; DOI=10.1038/77964;
RA   Sharma V., Sharma S., zu Bentrup K.H., McKinney J.D., Russell D.G.,
RA   Jacobs W.R. Jr., Sacchettini J.C.;
RT   "Structure of isocitrate lyase, a persistence factor of Mycobacterium
RT   tuberculosis.";
RL   Nat. Struct. Biol. 7:663-668(2000).
RN   [8]
RP   INDUCTION.
RC   STRAIN=ATCC 25618 / H37Rv;
RX   PubMed=19767422; DOI=10.1128/jb.01009-09;
RA   Micklinghoff J.C., Breitinger K.J., Schmidt M., Geffers R., Eikmanns B.J.,
RA   Bange F.C.;
RT   "Role of the transcriptional regulator RamB (Rv0465c) in the control of the
RT   glyoxylate cycle in Mycobacterium tuberculosis.";
RL   J. Bacteriol. 191:7260-7269(2009).
RN   [9]
RP   INDUCTION.
RC   STRAIN=H37Rv;
RX   PubMed=22916289; DOI=10.1371/journal.pone.0043651;
RA   Masiewicz P., Brzostek A., Wolanski M., Dziadek J.,
RA   Zakrzewska-Czerwinska J.;
RT   "A novel role of the PrpR as a transcription factor involved in the
RT   regulation of methylcitrate pathway in Mycobacterium tuberculosis.";
RL   PLoS ONE 7:E43651-E43651(2012).
CC   -!- FUNCTION: Involved in the persistence and virulence of M.tuberculosis.
CC       Catalyzes the reversible formation of succinate and glyoxylate from
CC       isocitrate, a key step of the glyoxylate cycle, which operates as an
CC       anaplerotic route for replenishing the tricarboxylic acid cycle during
CC       growth on fatty acid substrates (PubMed:10932251, PubMed:10963599,
CC       PubMed:18275086, PubMed:24354272). It could also catalyze the formation
CC       of pyruvate and succinate from 2-methylisocitrate, a key step in the
CC       methylcitrate cycle (propionate degradation route) (By similarity).
CC       {ECO:0000250|UniProtKB:P9WKK6, ECO:0000269|PubMed:10932251,
CC       ECO:0000269|PubMed:10963599, ECO:0000269|PubMed:18275086,
CC       ECO:0000269|PubMed:24354272}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=D-threo-isocitrate = glyoxylate + succinate;
CC         Xref=Rhea:RHEA:13245, ChEBI:CHEBI:15562, ChEBI:CHEBI:30031,
CC         ChEBI:CHEBI:36655; EC=4.1.3.1;
CC         Evidence={ECO:0000269|PubMed:24354272};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:10932251, ECO:0000269|PubMed:18275086};
CC       Note=Can also use Mn(2+) ion. {ECO:0000269|PubMed:18275086};
CC   -!- ACTIVITY REGULATION: Inhibited by 3-nitropropionate (3-NP) and 3-
CC       bromopyruvate when M.tuberculosis grows on acetate, but not on glucose.
CC       Inhibition of ICL by 3-bromopyruvate is accomplished via dehalogenation
CC       of the inhibitor to form a covalent adduct with the active site Cys-
CC       191. Also inhibited by zinc and calcium ions.
CC       {ECO:0000269|PubMed:10932251, ECO:0000269|PubMed:18275086,
CC       ECO:0000269|PubMed:24354272}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=45 uM for isocitrate (at pH 7 and 37 degrees Celsius)
CC         {ECO:0000269|PubMed:24354272};
CC         KM=140 uM for glyoxylate (at pH 7 and 37 degrees Celsius)
CC         {ECO:0000269|PubMed:24354272};
CC         KM=412 uM for succinate (at pH 7 and 37 degrees Celsius)
CC         {ECO:0000269|PubMed:24354272};
CC         Note=kcat is 12.2 sec(-1) for isocitrate lyase activity with
CC         isocitrate as substrate(at pH 7 and 37 degrees Celsius). kcat is 8.5
CC         sec(-1) for isocitrate lyase activity with succinate as substrate(at
CC         pH 7 and 37 degrees Celsius). {ECO:0000269|PubMed:24354272};
CC   -!- PATHWAY: Carbohydrate metabolism; glyoxylate cycle; (S)-malate from
CC       isocitrate: step 1/2. {ECO:0000305|PubMed:10963599}.
CC   -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:10932251}.
CC   -!- INDUCTION: Activated by PrpR and repressed by RamB.
CC       {ECO:0000269|PubMed:19767422, ECO:0000269|PubMed:22916289}.
CC   -!- PTM: Pupylated at Lys-334 by the prokaryotic ubiquitin-like protein
CC       Pup, which leads to its degradation by the proteasome.
CC       {ECO:0000269|PubMed:20066036}.
CC   -!- DISRUPTION PHENOTYPE: Cells lacking this gene show an attenuated
CC       bacterial persistence and virulence in immune-competent mice without
CC       affecting bacterial growth during the acute phase of infection.
CC       {ECO:0000269|PubMed:10963599}.
CC   -!- MISCELLANEOUS: Was identified as a natural substrate of the
CC       M.tuberculosis proteasome. {ECO:0000269|PubMed:20066036}.
CC   -!- SIMILARITY: Belongs to the isocitrate lyase/PEP mutase superfamily.
CC       Isocitrate lyase family. {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; AL123456; CCP43200.1; -; Genomic_DNA.
DR   PIR; G70828; G70828.
DR   RefSeq; WP_003402316.1; NZ_NVQJ01000002.1.
DR   RefSeq; YP_177728.1; NC_000962.3.
DR   PDB; 1F61; X-ray; 2.00 A; A/B=2-428.
DR   PDB; 1F8I; X-ray; 2.25 A; A/B/C/D=2-428.
DR   PDB; 1F8M; X-ray; 1.80 A; A/B/C/D=2-428.
DR   PDB; 5DQL; X-ray; 1.78 A; A/B/C/D=1-428.
DR   PDB; 6C4A; X-ray; 1.80 A; A/B/C/D/E/F/G/H=1-428.
DR   PDB; 6C4C; X-ray; 2.20 A; A/B/C/D/E/F/G/H=1-428.
DR   PDB; 6VB9; X-ray; 1.88 A; A/B/C/D=1-428.
DR   PDB; 6WSI; X-ray; 1.75 A; A/B/C/D=1-428.
DR   PDB; 6XPP; X-ray; 1.55 A; A/B/C/D=1-428.
DR   PDB; 7CP1; X-ray; 2.58 A; A/B=1-428.
DR   PDB; 7RB1; X-ray; 1.90 A; A/B/C/D=1-428.
DR   PDBsum; 1F61; -.
DR   PDBsum; 1F8I; -.
DR   PDBsum; 1F8M; -.
DR   PDBsum; 5DQL; -.
DR   PDBsum; 6C4A; -.
DR   PDBsum; 6C4C; -.
DR   PDBsum; 6VB9; -.
DR   PDBsum; 6WSI; -.
DR   PDBsum; 6XPP; -.
DR   PDBsum; 7CP1; -.
DR   PDBsum; 7RB1; -.
DR   AlphaFoldDB; P9WKK7; -.
DR   SMR; P9WKK7; -.
DR   STRING; 83332.Rv0467; -.
DR   BindingDB; P9WKK7; -.
DR   ChEMBL; CHEMBL1667699; -.
DR   DrugBank; DB04343; Glyoxylic acid.
DR   PaxDb; 83332-Rv0467; -.
DR   ABCD; P9WKK7; 1 sequenced antibody.
DR   DNASU; 886291; -.
DR   GeneID; 45424429; -.
DR   GeneID; 886291; -.
DR   KEGG; mtu:Rv0467; -.
DR   TubercuList; Rv0467; -.
DR   eggNOG; COG2224; Bacteria.
DR   InParanoid; P9WKK7; -.
DR   OrthoDB; 8629576at2; -.
DR   PhylomeDB; P9WKK7; -.
DR   BioCyc; MetaCyc:G185E-4594-MONOMER; -.
DR   BRENDA; 4.1.3.1; 3445.
DR   UniPathway; UPA00703; UER00719.
DR   Proteomes; UP000001584; Chromosome.
DR   GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR   GO; GO:0005576; C:extracellular region; IDA:CAFA.
DR   GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR   GO; GO:0004451; F:isocitrate lyase activity; IDA:MTBBASE.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0046421; F:methylisocitrate lyase activity; IDA:MTBBASE.
DR   GO; GO:0035375; F:zymogen binding; IPI:CAFA.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEP:MTBBASE.
DR   GO; GO:0006097; P:glyoxylate cycle; IDA:MTBBASE.
DR   GO; GO:0006102; P:isocitrate metabolic process; IDA:MTBBASE.
DR   GO; GO:0052572; P:response to host immune response; IEP:MTBBASE.
DR   GO; GO:0006099; P:tricarboxylic acid cycle; IEA:UniProtKB-KW.
DR   CDD; cd06556; ICL_KPHMT; 1.
DR   Gene3D; 3.20.20.60; Phosphoenolpyruvate-binding domains; 1.
DR   InterPro; IPR006254; Isocitrate_lyase.
DR   InterPro; IPR018523; Isocitrate_lyase_ph_CS.
DR   InterPro; IPR015813; Pyrv/PenolPyrv_Kinase-like_dom.
DR   InterPro; IPR040442; Pyrv_Kinase-like_dom_sf.
DR   NCBIfam; TIGR01346; isocit_lyase; 2.
DR   PANTHER; PTHR21631:SF3; BIFUNCTIONAL GLYOXYLATE CYCLE PROTEIN; 1.
DR   PANTHER; PTHR21631; ISOCITRATE LYASE/MALATE SYNTHASE; 1.
DR   Pfam; PF00463; ICL; 2.
DR   PIRSF; PIRSF001362; Isocit_lyase; 1.
DR   SUPFAM; SSF51621; Phosphoenolpyruvate/pyruvate domain; 1.
DR   PROSITE; PS00161; ISOCITRATE_LYASE; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Glyoxylate bypass; Isopeptide bond; Lyase; Magnesium;
KW   Manganese; Metal-binding; Reference proteome; Tricarboxylic acid cycle;
KW   Ubl conjugation.
FT   CHAIN           1..428
FT                   /note="Isocitrate lyase"
FT                   /id="PRO_0000068779"
FT   ACT_SITE        191
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000305|PubMed:24354272"
FT   BINDING         91..93
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   BINDING         153
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   BINDING         192..193
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   BINDING         228
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   BINDING         313..317
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   BINDING         347
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   CROSSLNK        334
FT                   /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT                   with Q-Cter in protein Pup)"
FT                   /evidence="ECO:0000269|PubMed:20066036"
FT   MUTAGEN         191
FT                   /note="C->S: Adopts a conformation almost identical to the
FT                   wild-type."
FT                   /evidence="ECO:0000269|PubMed:10932251"
FT   HELIX           10..19
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           21..23
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           32..37
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           47..62
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          66..70
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           74..82
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          88..90
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           92..98
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          108..110
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           116..138
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          142..144
FT                   /evidence="ECO:0007829|PDB:7RB1"
FT   STRAND          150..153
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   TURN            155..158
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           161..173
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          177..184
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           186..188
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           202..218
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          224..229
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   TURN            231..233
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          236..238
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   TURN            243..245
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           246..248
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          249..253
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          259..261
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           265..275
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           276..278
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          280..284
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           291..304
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          309..313
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          316..318
FT                   /evidence="ECO:0007829|PDB:1F61"
FT   HELIX           320..323
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           326..338
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   STRAND          341..346
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           349..368
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           370..383
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           384..386
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           393..396
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           399..409
FT                   /evidence="ECO:0007829|PDB:6XPP"
FT   HELIX           422..426
FT                   /evidence="ECO:0007829|PDB:6XPP"
SQ   SEQUENCE   428 AA;  47087 MW;  E5223F38CB5D9E8B CRC64;
     MSVVGTPKSA EQIQQEWDTN PRWKDVTRTY SAEDVVALQG SVVEEHTLAR RGAEVLWEQL
     HDLEWVNALG ALTGNMAVQQ VRAGLKAIYL SGWQVAGDAN LSGHTYPDQS LYPANSVPQV
     VRRINNALQR ADQIAKIEGD TSVENWLAPI VADGEAGFGG ALNVYELQKA LIAAGVAGSH
     WEDQLASEKK CGHLGGKVLI PTQQHIRTLT SARLAADVAD VPTVVIARTD AEAATLITSD
     VDERDQPFIT GERTREGFYR TKNGIEPCIA RAKAYAPFAD LIWMETGTPD LEAARQFSEA
     VKAEYPDQML AYNCSPSFNW KKHLDDATIA KFQKELAAMG FKFQFITLAG FHALNYSMFD
     LAYGYAQNQM SAYVELQERE FAAEERGYTA TKHQREVGAG YFDRIATTVD PNSSTTALTG
     STEEGQFH
//