ACEA_MYCTU
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 03-AUG-2022, entry version 43.
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; Actinobacteria; Corynebacteriales; 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.m111.011627;
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}.
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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; 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; 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; P9WKK7; -.
DR DNASU; 886291; -.
DR GeneID; 45424429; -.
DR GeneID; 886291; -.
DR KEGG; mtu:Rv0467; -.
DR TubercuList; Rv0467; -.
DR eggNOG; COG2224; Bacteria.
DR OMA; LEKDWAE; -.
DR PhylomeDB; P9WKK7; -.
DR BioCyc; MetaCyc:G185E-4594-MON; -.
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 Gene3D; 3.20.20.60; -; 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 PANTHER; PTHR21631; PTHR21631; 1.
DR Pfam; PF00463; ICL; 2.
DR PIRSF; PIRSF001362; Isocit_lyase; 1.
DR SUPFAM; SSF51621; SSF51621; 1.
DR TIGRFAMs; TIGR01346; isocit_lyase; 2.
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
