ID   EGTA_MYCTO              Reviewed;         432 AA.
AC   P9WPK6; L0TDK0; O69672; Q7D512;
DT   16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT   16-APR-2014, sequence version 1.
DT   25-MAY-2022, entry version 43.
DE   RecName: Full=Glutamate--cysteine ligase EgtA;
DE            EC=6.3.2.2 {ECO:0000250|UniProtKB:P9WPK7};
DE   AltName: Full=Gamma-glutamylcysteine synthetase;
DE            Short=GCS;
DE            Short=Gamma-ECS;
GN   Name=egtA; OrderedLocusNames=MT3807;
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, PATHWAY, INDUCTION, OPERON STRUCTURE, AND DISRUPTION PHENOTYPE.
RC   STRAIN=CDC 1551 / Oshkosh;
RX   PubMed=26774486; DOI=10.1016/j.celrep.2015.12.056;
RA   Saini V., Cumming B.M., Guidry L., Lamprecht D.A., Adamson J.H.,
RA   Reddy V.P., Chinta K.C., Mazorodze J.H., Glasgow J.N.,
RA   Richard-Greenblatt M., Gomez-Velasco A., Bach H., Av-Gay Y., Eoh H.,
RA   Rhee K., Steyn A.J.;
RT   "Ergothioneine maintains redox and bioenergetic homeostasis essential for
RT   drug susceptibility and virulence of Mycobacterium tuberculosis.";
RL   Cell Rep. 14:572-585(2016).
CC   -!- FUNCTION: Catalyzes the synthesis of gamma-glutamylcysteine (gamma-GC)
CC       which is used as substrate for the biosynthesis of the low-molecular
CC       thiol compound ergothioneine (ERG) (By similarity). ERG is one of the
CC       major redox buffers which protects bacteria against redox stressors and
CC       antibiotics; loss of ERG or mycothiol (MSH, the other major redox
CC       buffer in this bacteria) leads to respiratory alterations and
CC       bioenergetic deficiencies that negatively impact virulence
CC       (PubMed:26774486). {ECO:0000250|UniProtKB:A0R5N1,
CC       ECO:0000250|UniProtKB:P9WPK7, ECO:0000305|PubMed:26774486}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-cysteine + L-glutamate = ADP + gamma-L-glutamyl-L-
CC         cysteine + H(+) + phosphate; Xref=Rhea:RHEA:13285, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:29985, ChEBI:CHEBI:30616, ChEBI:CHEBI:35235,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:58173, ChEBI:CHEBI:456216; EC=6.3.2.2;
CC         Evidence={ECO:0000250|UniProtKB:P9WPK7};
CC   -!- PATHWAY: Amino-acid biosynthesis; ergothioneine biosynthesis.
CC       {ECO:0000250|UniProtKB:A0R5N1, ECO:0000305|PubMed:26774486}.
CC   -!- INDUCTION: Expressed in log phase, part of the egtA-egtB-egtC-egtD
CC       operon, which does not include egtE (PubMed:26774486).
CC       {ECO:0000269|PubMed:26774486}.
CC   -!- DISRUPTION PHENOTYPE: Loss of production of ergothioneine (ERG), no
CC       alteration in ratio of oxidized versus reduced mycothiol (MSH), 25-fold
CC       increase in reactive oxygen species-producing cells, decreased
CC       resistance to compounds that cause oxidative stress, decreased
CC       resistance to the antibiotics rifampicin, isoniazid, bedaquiline and
CC       clofazimine (PubMed:26774486). Increased oxygen consumption and
CC       extracellular acidification rates, which are further increased by
CC       membrane uncoupler CCCP, indicative of electron chain dysfunction in
CC       the absence of ERG (PubMed:26774486). Absence leads to alteration of
CC       transcript levels for 68 genes which probably compensate for loss of
CC       redox control (PubMed:26774486). Decreased bacterial survival in mouse
CC       macrophage cell line, 10,000-fold decreased bacterial burden in
CC       infected mice lungs (strain BALB/c), no alteration in mouse lung ERG
CC       levels (PubMed:26774486). {ECO:0000269|PubMed:26774486}.
CC   -!- SIMILARITY: Belongs to the glutamate--cysteine ligase type 2 family.
CC       EgtA subfamily. {ECO:0000305}.
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DR   EMBL; AE000516; AAK48174.1; -; Genomic_DNA.
DR   PIR; A70794; A70794.
DR   RefSeq; WP_003419809.1; NZ_KK341227.1.
DR   AlphaFoldDB; P9WPK6; -.
DR   SMR; P9WPK6; -.
DR   EnsemblBacteria; AAK48174; AAK48174; MT3807.
DR   KEGG; mtc:MT3807; -.
DR   PATRIC; fig|83331.31.peg.4099; -.
DR   HOGENOM; CLU_037109_0_0_11; -.
DR   UniPathway; UPA01014; -.
DR   Proteomes; UP000001020; Chromosome.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0004357; F:glutamate-cysteine ligase activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0052699; P:ergothioneine biosynthetic process; IEA:UniProtKB-UniRule.
DR   GO; GO:0006750; P:glutathione biosynthetic process; IEA:InterPro.
DR   HAMAP; MF_02034; EgtA; 1.
DR   InterPro; IPR017809; EgtA_Actinobacteria.
DR   InterPro; IPR035434; GCL_bact_plant.
DR   InterPro; IPR006336; GCS2.
DR   InterPro; IPR014746; Gln_synth/guanido_kin_cat_dom.
DR   InterPro; IPR011556; Glut_cys_lig_pln_type.
DR   PANTHER; PTHR34378; PTHR34378; 1.
DR   PANTHER; PTHR34378:SF1; PTHR34378:SF1; 1.
DR   Pfam; PF04107; GCS2; 1.
DR   PIRSF; PIRSF017901; GCL; 1.
DR   SUPFAM; SSF55931; SSF55931; 1.
DR   TIGRFAMs; TIGR03444; EgtA_Cys_ligase; 1.
PE   2: Evidence at transcript level;
KW   ATP-binding; Ligase; Nucleotide-binding.
FT   CHAIN           1..432
FT                   /note="Glutamate--cysteine ligase EgtA"
FT                   /id="PRO_0000426935"
SQ   SEQUENCE   432 AA;  45795 MW;  FACD5FDFAACC44FD CRC64;
     MTLAAMTAAA SQLDNAAPDD VEITDSSAAA EYIADGCLVD GPLGRVGLEM EAHCFDPADP
     FRRPSWEEIT EVLEWLSPLP GGSVVSVEPG GAVELSGPPA DGVLAAIGAM TRDQAVLRSA
     LANAGLGLVF LGADPLRSPV RVNPGARYRA MEQFFAASHS GVPGAAMMTS TAAIQVNLDA
     GPQEGWAERV RLAHALGPTM IAIAANSPML GGRFSGWQST RQRVWGQMDS ARCGPILGAS
     GDHPGIDWAK YALKAPVMMV RSPDTQDTRA VTDYVPFTDW VDGRVLLDGR RATVADLVYH
     LTTLFPPVRP RQWLEIRYLD SVPDEVWPAV VFTLVTLLDD PVAADLAVDA VEPVATAWDT
     AARIGLADRR LYLAANRCLA IAARRVPTEL IGAMQRLVDH VDRGVCPADD FSDRVIAGGI
     ASAVTGMMHG AS