ETHA_MYCTO
ID ETHA_MYCTO Reviewed; 489 AA.
AC P9WNF8; L0TDR6; P96223; Q7D4Q8;
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=FAD-containing monooxygenase EthA;
DE EC=1.14.13.- {ECO:0000250|UniProtKB:P9WNF9};
DE AltName: Full=Baeyer-Villiger monooxygenase EtaA;
DE Short=BVMO;
DE AltName: Full=Prodrug activator EtaA;
GN Name=ethA; Synonyms=etaA; OrderedLocusNames=MT3969;
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).
CC -!- FUNCTION: Monooxygenase able to convert a wide range of ketones to the
CC corresponding esters or lactones via a Baeyer-Villiger oxidation
CC reaction. Can act on long-chain aliphatic ketones (2-hexanone to 2-
CC dodecanone) and on aromatic ketones (phenylacetone and benzylacetone).
CC Is also able to catalyze enantioselective sulfoxidation of methyl-p-
CC tolylsulfide. In vivo, likely functions as a BVMO, but the exact nature
CC of the physiological substrate(s) remains to be established.
CC {ECO:0000250|UniProtKB:P9WNF9}.
CC -!- FUNCTION: Is responsible for the activation of several thiocarbamide-
CC containing pro-drugs into cytotoxic species. Thus, catalyzes the
CC oxidation of the antitubercular pro-drug ethionamide (ETH) to the
CC corresponding sulfoxide, which is further oxidized by EthA to 2-ethyl-
CC 4-amidopyridine, presumably via the unstable doubly oxidized sulfinic
CC acid intermediate; the final metabolite 2-ethyl-4-amidopyridine has no
CC antitubercular activity, so the cytotoxic species is a metabolite
CC intermediate formed by EthA. Also oxidizes thiacetazone (TAC),
CC thiobenzamide, and isothionicotinamide and thus is probably
CC responsible, as suggested by the observation of crossover resistance,
CC for the oxidative activation of these other thioamide antitubercular
CC drugs. {ECO:0000250|UniProtKB:P9WNF9}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ethionamide + H(+) + NADPH + O2 = ethionamide S-oxide + H2O +
CC NADP(+); Xref=Rhea:RHEA:47616, ChEBI:CHEBI:4885, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:87805;
CC Evidence={ECO:0000250|UniProtKB:P9WNF9};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P9WNF9};
CC Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:P9WNF9};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P9WNF9}.
CC Note=Is most likely membrane-associated.
CC {ECO:0000250|UniProtKB:P9WNF9}.
CC -!- INDUCTION: Repressed by the transcriptional regulator EthR.
CC {ECO:0000250|UniProtKB:P9WNF9}.
CC -!- SIMILARITY: Belongs to the FAD-binding monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; AE000516; AAK48336.1; -; Genomic_DNA.
DR PIR; C70655; C70655.
DR RefSeq; WP_003899731.1; NZ_KK341227.1.
DR AlphaFoldDB; P9WNF8; -.
DR SMR; P9WNF8; -.
DR EnsemblBacteria; AAK48336; AAK48336; MT3969.
DR KEGG; mtc:MT3969; -.
DR PATRIC; fig|83331.31.peg.4268; -.
DR HOGENOM; CLU_032067_2_0_11; -.
DR Proteomes; UP000001020; Chromosome.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0004499; F:N,N-dimethylaniline monooxygenase activity; IEA:InterPro.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR Gene3D; 3.50.50.60; -; 3.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR020946; Flavin_mOase-like.
DR Pfam; PF00743; FMO-like; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 3: Inferred from homology;
KW Cell membrane; FAD; Flavoprotein; Membrane; Monooxygenase; NADP;
KW Oxidoreductase.
FT CHAIN 1..489
FT /note="FAD-containing monooxygenase EthA"
FT /id="PRO_0000427134"
FT BINDING 15
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 36
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 44..47
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 54..56
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 56
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 104
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 183..189
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT BINDING 207..208
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
FT SITE 292
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000250|UniProtKB:Q47PU3"
SQ SEQUENCE 489 AA; 55326 MW; 844611B7E831180D CRC64;
MTEHLDVVIV GAGISGVSAA WHLQDRCPTK SYAILEKRES MGGTWDLFRY PGIRSDSDMY
TLGFRFRPWT GRQAIADGKP ILEYVKSTAA MYGIDRHIRF HHKVISADWS TAENRWTVHI
QSHGTLSALT CEFLFLCSGY YNYDEGYSPR FAGSEDFVGP IIHPQHWPED LDYDAKNIVV
IGSGATAVTL VPALADSGAK HVTMLQRSPT YIVSQPDRDG IAEKLNRWLP ETMAYTAVRW
KNVLRQAAVY SACQKWPRRM RKMFLSLIQR QLPEGYDVRK HFGPHYNPWD QRLCLVPNGD
LFRAIRHGKV EVVTDTIERF TATGIRLNSG RELPADIIIT ATGLNLQLFG GATATIDGQQ
VDITTTMAYK GMMLSGIPNM AYTVGYTNAS WTLKADLVSE FVCRLLNYMD DNGFDTVVVE
RPGSDVEERP FMEFTPGYVL RSLDELPKQG SRTPWRLNQN YLRDIRLIRR GKIDDEGLRF
AKRPAPVGV
