ACEA1_MYCTO
ID ACEA1_MYCTO Reviewed; 428 AA.
AC P9WKK6; 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 41.
DE RecName: Full=Isocitrate lyase 1 {ECO:0000303|PubMed:10572116};
DE Short=ICL1 {ECO:0000303|PubMed:10572116};
DE EC=4.1.3.1 {ECO:0000269|PubMed:10572116, ECO:0000269|PubMed:16879647};
DE AltName: Full=Isocitrase {ECO:0000303|PubMed:10572116};
DE AltName: Full=Isocitratase {ECO:0000303|PubMed:10572116};
DE AltName: Full=Methylisocitrate lyase {ECO:0000303|PubMed:16879647};
DE Short=MICA {ECO:0000303|PubMed:16879647};
DE EC=4.1.3.30 {ECO:0000269|PubMed:16879647};
GN Name=icl1; OrderedLocusNames=MT0483;
OS Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83331;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CDC 1551 / Oshkosh;
RX PubMed=12218036; DOI=10.1128/jb.184.19.5479-5490.2002;
RA Fleischmann R.D., Alland D., Eisen J.A., Carpenter L., White O.,
RA Peterson J.D., DeBoy R.T., Dodson R.J., Gwinn M.L., Haft D.H., Hickey E.K.,
RA Kolonay J.F., Nelson W.C., Umayam L.A., Ermolaeva M.D., Salzberg S.L.,
RA Delcher A., Utterback T.R., Weidman J.F., Khouri H.M., Gill J., Mikula A.,
RA Bishai W., Jacobs W.R. Jr., Venter J.C., Fraser C.M.;
RT "Whole-genome comparison of Mycobacterium tuberculosis clinical and
RT laboratory strains.";
RL J. Bacteriol. 184:5479-5490(2002).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, INDUCTION, AND COFACTOR.
RC STRAIN=CDC 1551 / Oshkosh;
RX PubMed=10572116; DOI=10.1128/jb.181.23.7161-7167.1999;
RA Honer Zu Bentrup K., Miczak A., Swenson D.L., Russell D.G.;
RT "Characterization of activity and expression of isocitrate lyase in
RT Mycobacterium avium and Mycobacterium tuberculosis.";
RL J. Bacteriol. 181:7161-7167(1999).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND ACTIVITY REGULATION.
RX PubMed=15895072; DOI=10.1038/nm1252;
RA Munoz-Elias E.J., McKinney J.D.;
RT "Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required
RT for in vivo growth and virulence.";
RL Nat. Med. 11:638-644(2005).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16879647; DOI=10.1111/j.1365-2958.2006.05297.x;
RA Gould T.A., van de Langemheen H., Munoz-Elias E.J., McKinney J.D.,
RA Sacchettini J.C.;
RT "Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles
RT in Mycobacterium tuberculosis.";
RL Mol. Microbiol. 61:940-947(2006).
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. It also catalyzes the formation of
CC pyruvate and succinate from 2-methylisocitrate, a key step in the
CC methylcitrate cycle (propionate degradation route).
CC {ECO:0000269|PubMed:10572116, ECO:0000269|PubMed:15895072,
CC ECO:0000269|PubMed:16879647}.
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; Evidence={ECO:0000269|PubMed:10572116,
CC ECO:0000269|PubMed:16879647};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate = pyruvate +
CC succinate; Xref=Rhea:RHEA:16809, ChEBI:CHEBI:15361,
CC ChEBI:CHEBI:30031, ChEBI:CHEBI:57429; EC=4.1.3.30;
CC Evidence={ECO:0000269|PubMed:16879647};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10572116};
CC Note=Can also use Mn(2+) ion. {ECO:0000269|PubMed:10572116};
CC -!- ACTIVITY REGULATION: Inhibited by itaconate, itaconic anhydride,
CC bromopyruvate and 3-nitropropionate (3-NP), when M.tuberculosis grows
CC on fatty acids, but not on glucose. At 5 mM, oxalate and malate also
CC inhibit the activity to approximately 50%.
CC {ECO:0000269|PubMed:10572116, ECO:0000269|PubMed:15895072}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=145 uM for threo-D-isocitrate (at pH 6.8 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:10572116};
CC KM=188 uM for threo-DL-isocitrate (ICA) (at pH 6.8)
CC {ECO:0000269|PubMed:16879647};
CC KM=718 uM for DL-threo-2-methylisocitrate (MICA) (at pH 7.5)
CC {ECO:0000269|PubMed:16879647};
CC Vmax=1.3 umol/min/mg enzyme with threo-D-isocitrate as substrate (at
CC pH 6.8 and 37 degrees Celsius) {ECO:0000269|PubMed:10572116};
CC Note=kcat is 5.24 sec(-1) for isocitrate lyase activity with threo-
CC DL-isocitrate as substrate (at pH 6). kcat is 1.25 sec(-1) for
CC methylisocitrate lyase activity with DL-threo-2-methylisocitrate as
CC substrate (at pH 7.5). {ECO:0000269|PubMed:16879647};
CC pH dependence:
CC Optimum pH is 6.8. {ECO:0000269|PubMed:10572116};
CC -!- PATHWAY: Carbohydrate metabolism; glyoxylate cycle; (S)-malate from
CC isocitrate: step 1/2. {ECO:0000305|PubMed:16879647}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P9WKK7}.
CC -!- INDUCTION: Induced by palmitate and acetate. Repressed by glucose and
CC succinate. {ECO:0000269|PubMed:10572116}.
CC -!- DISRUPTION PHENOTYPE: Deletion of icl1 has little effect on replication
CC in media containing glycerol, glucose, short-chain fatty acids or long-
CC chain fatty acids. Deletion of icl1 results in a modest reduction of
CC the bacterial load in the lungs during the chronic phase but not the
CC acute phase of infection, and reduces tissue pathology. Deletion of
CC both icl1 and icl2 eliminates growth on fatty acids but has little
CC effect on use of carbohydrates. Cells lacking both genes are incapable
CC of growth in mice and are rapidly eliminated from the lungs and spleen.
CC {ECO:0000269|PubMed:15895072}.
CC -!- SIMILARITY: Belongs to the isocitrate lyase/PEP mutase superfamily.
CC Isocitrate lyase family. {ECO:0000305}.
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DR EMBL; AE000516; AAK44707.1; -; Genomic_DNA.
DR PIR; G70828; G70828.
DR RefSeq; WP_003402316.1; NZ_KK341227.1.
DR AlphaFoldDB; P9WKK6; -.
DR SMR; P9WKK6; -.
DR ChEMBL; CHEMBL4295587; -.
DR EnsemblBacteria; AAK44707; AAK44707; MT0483.
DR GeneID; 45424429; -.
DR KEGG; mtc:MT0483; -.
DR PATRIC; fig|83331.31.peg.513; -.
DR HOGENOM; CLU_019214_2_0_11; -.
DR UniPathway; UPA00703; UER00719.
DR Proteomes; UP000001020; Chromosome.
DR GO; GO:0004451; F:isocitrate lyase activity; IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046421; F:methylisocitrate lyase activity; IEA:UniProtKB-EC.
DR GO; GO:0006097; P:glyoxylate cycle; IEA:UniProtKB-UniPathway.
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 Glyoxylate bypass; Lyase; Magnesium; Manganese; Metal-binding;
KW Tricarboxylic acid cycle.
FT CHAIN 1..428
FT /note="Isocitrate lyase 1"
FT /id="PRO_0000427637"
FT ACT_SITE 191
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 91..93
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 153
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 192..193
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 228
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 313..317
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
FT BINDING 347
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P9WKK7"
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
