TRXB_MYCTU
ID TRXB_MYCTU Reviewed; 335 AA.
AC P9WHH1; L0TFM3; O53592; P52214;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 47.
DE RecName: Full=Thioredoxin reductase {ECO:0000303|Ref.1};
DE Short=TR;
DE Short=TRXR;
DE EC=1.8.1.9 {ECO:0000269|PubMed:16301794};
GN Name=trxB;
GN Synonyms=trxB2 {ECO:0000303|PubMed:11567012, ECO:0000303|PubMed:9634230},
GN trxR {ECO:0000303|PubMed:16301794}; OrderedLocusNames=Rv3913;
GN ORFNames=MTV028.04;
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 [GENOMIC DNA].
RA Wieles B., Phillip W., Drijfhout J.W., Offringa R., Ottenhoff T.H.M.;
RT "Sequence analysis and functional characterization of thioredoxin and
RT thioredoxin reductase of Mycobacterium tuberculosis.";
RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
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 [3]
RP INDUCTION BY SIGH.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11567012; DOI=10.1128/jb.183.20.6119-6125.2001;
RA Raman S., Song T., Puyang X., Bardarov S., Jacobs W.R. Jr., Husson R.N.;
RT "The alternative sigma factor SigH regulates major components of oxidative
RT and heat stress responses in Mycobacterium tuberculosis.";
RL J. Bacteriol. 183:6119-6125(2001).
RN [4]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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, AND DISRUPTION PHENOTYPE.
RX PubMed=27249779; DOI=10.1371/journal.ppat.1005675;
RA Lin K., O'Brien K.M., Trujillo C., Wang R., Wallach J.B., Schnappinger D.,
RA Ehrt S.;
RT "Mycobacterium tuberculosis thioredoxin reductase is essential for thiol
RT redox homeostasis but plays a minor role in antioxidant defense.";
RL PLoS Pathog. 12:e1005675-e1005675(2016).
RN [7]
RP PHOSPHORYLATION AT TYR-32, AND MUTAGENESIS OF TYR-32.
RX PubMed=29317718; DOI=10.1038/s41598-017-18547-9;
RA Wong D., Li W., Chao J.D., Zhou P., Narula G., Tsui C., Ko M., Xie J.,
RA Martinez-Frailes C., Av-Gay Y.;
RT "Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis
RT growth in macrophages.";
RL Sci. Rep. 8:155-155(2018).
RN [8] {ECO:0007744|PDB:2A87}
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) IN COMPLEX WITH FAD AND NADP,
RP CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=16301794; DOI=10.1107/s0907444905030519;
RA Akif M., Suhre K., Verma C., Mande S.C.;
RT "Conformational flexibility of Mycobacterium tuberculosis thioredoxin
RT reductase: crystal structure and normal-mode analysis.";
RL Acta Crystallogr. D 61:1603-1611(2005).
CC -!- FUNCTION: Essential thiol-reducing enzyme that protects the cell from
CC thiol-specific oxidizing stress. Plays a minor role in defense against
CC oxidative and nitrosative stress. Is essential to establish and
CC maintain infection in mice. {ECO:0000269|PubMed:27249779}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide +
CC H(+) + NADPH; Xref=Rhea:RHEA:20345, Rhea:RHEA-COMP:10698, Rhea:RHEA-
CC COMP:10700, ChEBI:CHEBI:15378, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.8.1.9;
CC Evidence={ECO:0000269|PubMed:16301794};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:16301794};
CC Note=Binds 1 FAD per subunit. {ECO:0000269|PubMed:16301794};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:16301794}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- INDUCTION: Expressed following oxidative stress under control of SigH.
CC {ECO:0000269|PubMed:11567012}.
CC -!- PTM: Phosphorylated on Tyr-32 by PtkA. {ECO:0000269|PubMed:29317718}.
CC -!- DISRUPTION PHENOTYPE: Essential, a deletion mutant cannot be isolated.
CC TrxB depletion inhibits mycobacterial growth and causes lytic death of
CC the cells. Depletion affects growth-essential processes, including
CC sulfur and DNA metabolism. Partially depleted cells are highly
CC susceptible to thiol-specific oxidizing stress, but not to peroxide and
CC reactive nitrogen species. Depleted cells are highly susceptible to the
CC cell wall biosynthesis inhibitors vancomycin and moenomycin. In vivo,
CC depletion of TrxB results in clearance of M.tuberculosis during both
CC the acute and chronic phases of infection.
CC {ECO:0000269|PubMed:27249779}.
CC -!- MISCELLANEOUS: The active site is a redox-active disulfide bond.
CC {ECO:0000269|PubMed:16301794}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000269|PubMed:19099550}.
CC -!- SIMILARITY: Belongs to the class-II pyridine nucleotide-disulfide
CC oxidoreductase family. {ECO:0000305}.
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DR EMBL; X95798; CAA65070.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP46742.1; -; Genomic_DNA.
DR PIR; A70851; A70851.
DR RefSeq; NP_218430.1; NC_000962.3.
DR RefSeq; WP_003900782.1; NZ_NVQJ01000005.1.
DR PDB; 2A87; X-ray; 3.00 A; A/B=1-335.
DR PDBsum; 2A87; -.
DR AlphaFoldDB; P9WHH1; -.
DR SMR; P9WHH1; -.
DR STRING; 83332.Rv3913; -.
DR BindingDB; P9WHH1; -.
DR ChEMBL; CHEMBL2390811; -.
DR iPTMnet; P9WHH1; -.
DR PaxDb; P9WHH1; -.
DR DNASU; 886232; -.
DR GeneID; 45427913; -.
DR GeneID; 886232; -.
DR KEGG; mtu:Rv3913; -.
DR TubercuList; Rv3913; -.
DR eggNOG; COG0492; Bacteria.
DR OMA; VDNFPGY; -.
DR PhylomeDB; P9WHH1; -.
DR Reactome; R-HSA-1222541; Cell redox homeostasis.
DR PRO; PR:P9WHH1; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:MTBBASE.
DR GO; GO:0070402; F:NADPH binding; IDA:MTBBASE.
DR GO; GO:0015035; F:protein-disulfide reductase activity; IDA:MTBBASE.
DR GO; GO:0004791; F:thioredoxin-disulfide reductase activity; IDA:MTBBASE.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:MTBBASE.
DR GO; GO:0019430; P:removal of superoxide radicals; IEA:InterPro.
DR GO; GO:0001666; P:response to hypoxia; IEP:MTBBASE.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR InterPro; IPR008255; Pyr_nucl-diS_OxRdtase_2_AS.
DR InterPro; IPR005982; Thioredox_Rdtase.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR TIGRFAMs; TIGR01292; TRX_reduct; 1.
DR PROSITE; PS00573; PYRIDINE_REDOX_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Disulfide bond; FAD; Flavoprotein;
KW NADP; Oxidoreductase; Phosphoprotein; Redox-active center;
KW Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:21969609"
FT CHAIN 2..335
FT /note="Thioredoxin reductase"
FT /id="PRO_0000166741"
FT BINDING 22..25
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 44..51
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 60
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 93
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 166
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 185
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 191
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 248
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 268
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 288
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 295..298
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT BINDING 295
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:16301794,
FT ECO:0007744|PDB:2A87"
FT MOD_RES 2
FT /note="N-acetylthreonine"
FT /evidence="ECO:0007744|PubMed:21969609"
FT MOD_RES 32
FT /note="Phosphotyrosine; by PtkA"
FT /evidence="ECO:0000269|PubMed:29317718"
FT DISULFID 145..148
FT /note="Redox-active"
FT /evidence="ECO:0000269|PubMed:16301794"
FT MUTAGEN 32
FT /note="Y->A: Significantly reduces phosphorylation."
FT /evidence="ECO:0000269|PubMed:29317718"
FT CONFLICT 125
FT /note="A -> R (in Ref. 1; CAA65070)"
FT /evidence="ECO:0000305"
FT CONFLICT 215
FT /note="V -> C (in Ref. 1; CAA65070)"
FT /evidence="ECO:0000305"
FT CONFLICT 228
FT /note="V -> Y (in Ref. 1; CAA65070)"
FT /evidence="ECO:0000305"
FT STRAND 15..20
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 23..35
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 41..43
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 51..53
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 70..83
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 87..89
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 93..97
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 99..107
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 112..120
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 124..126
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 133..136
FT /evidence="ECO:0007829|PDB:2A87"
FT TURN 139..141
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 146..149
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 150..153
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 157..161
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 165..174
FT /evidence="ECO:0007829|PDB:2A87"
FT TURN 175..177
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 179..184
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 186..189
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 196..202
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 206..209
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 211..218
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 237..239
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 244..246
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 250..252
FT /evidence="ECO:0007829|PDB:2A87"
FT TURN 255..257
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 275..277
FT /evidence="ECO:0007829|PDB:2A87"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 287..289
FT /evidence="ECO:0007829|PDB:2A87"
FT HELIX 297..320
FT /evidence="ECO:0007829|PDB:2A87"
SQ SEQUENCE 335 AA; 35643 MW; 3D0DD581E6C187E2 CRC64;
MTAPPVHDRA HHPVRDVIVI GSGPAGYTAA LYAARAQLAP LVFEGTSFGG ALMTTTDVEN
YPGFRNGITG PELMDEMREQ ALRFGADLRM EDVESVSLHG PLKSVVTADG QTHRARAVIL
AMGAAARYLQ VPGEQELLGR GVSSCATCDG FFFRDQDIAV IGGGDSAMEE ATFLTRFARS
VTLVHRRDEF RASKIMLDRA RNNDKIRFLT NHTVVAVDGD TTVTGLRVRD TNTGAETTLP
VTGVFVAIGH EPRSGLVREA IDVDPDGYVL VQGRTTSTSL PGVFAAGDLV DRTYRQAVTA
AGSGCAAAID AERWLAEHAA TGEADSTDAL IGAQR
