DOXA_STRC0
ID DOXA_STRC0 Reviewed; 420 AA.
AC Q93MI2;
DT 19-MAR-2014, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 71.
DE RecName: Full=Cytochrome P-450 monooxygenase DoxA;
DE EC=1.14.13.181 {ECO:0000269|PubMed:5365804};
DE AltName: Full=13-deoxycarminomycin C-13 hydroxylase;
DE AltName: Full=13-deoxydaunorubicin C-13 hydroxylase;
DE AltName: Full=13-dihydrocarminomycin C-13 hydroxylase;
DE AltName: Full=13-dihydrodaunorubicin C-13 hydroxylase;
DE AltName: Full=Daunorubicin C-14 hydroxylase;
GN Name=doxA;
OS Streptomyces peucetius subsp. caesius.
OC Bacteria; Actinobacteria; Streptomycetales; Streptomycetaceae;
OC Streptomyces.
OX NCBI_TaxID=55158;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=ATCC 27952 / DSM 41231 / NBRC 14660 / 106FI;
RA Hong Y.-S., Kim H.S., Lee J.-H., Kim K.-W., Lee J.J.;
RT "Molecular cloning and characterization of the doxA cytochrome P-450
RT hydroxylase gene in Streptomyces peucetius subsp. caesius ATCC 27952.";
RL J. Microbiol. Biotechnol. 11:895-898(2001).
RN [2]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RC STRAIN=ATCC 27952 / DSM 41231 / NBRC 14660 / 106FI;
RX PubMed=5365804; DOI=10.1002/bit.260110607;
RA Arcamone F., Cassinelli G., Fantini G., Grein A., Orezzi P., Pol C.,
RA Spalla C.;
RT "Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S.
RT peucetius var. caesius.";
RL Biotechnol. Bioeng. 11:1101-1110(1969).
CC -!- FUNCTION: Involved in the biosynthesis of the anthracyclines
CC carminomycin, daunorubicin (daunomycin) and doxorubicin (adriamycin)
CC which are aromatic polyketide antibiotics that exhibit high
CC cytotoxicity and are widely applied in the chemotherapy of a variety of
CC cancers. In vivo, DoxA catalyzes the C-13 hydroxylation of 13-
CC deoxycarminomycin and 13-deoxydaunorubicin to yield 13-
CC dihydrocarminomycin and 13-dihydrodaunorubicin, respectively, as well
CC as the oxidation of these 13-dihydro-anthracyclines to their respective
CC 13-keto forms, carminomycin and daunorubicin. In vivo, it also
CC catalyzes the C-14 hydroxylation of daunorubicin to form doxorubicin.
CC It can only use NADP. DoxA acts jointly with DnrV.
CC {ECO:0000269|PubMed:5365804, ECO:0000269|Ref.1}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=13-deoxydaunorubicin + H(+) + NADPH + O2 = 13-
CC dihydrodaunorubicin + H2O + NADP(+); Xref=Rhea:RHEA:37851,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:75296,
CC ChEBI:CHEBI:75297; EC=1.14.13.181;
CC Evidence={ECO:0000269|PubMed:5365804};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=13-dihydrodaunorubicin + H(+) + NADPH + O2 = daunorubicin + 2
CC H2O + NADP(+); Xref=Rhea:RHEA:37847, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:64677, ChEBI:CHEBI:75296;
CC EC=1.14.13.181; Evidence={ECO:0000269|PubMed:5365804};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=13-deoxycarminomycin + H(+) + NADPH + O2 = 13-
CC dihydrocarminomycin + H2O + NADP(+); Xref=Rhea:RHEA:56360,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:140329,
CC ChEBI:CHEBI:140330; Evidence={ECO:0000269|PubMed:5365804};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=13-dihydrocarminomycin + H(+) + NADPH + O2 = carminomycin + 2
CC H2O + NADP(+); Xref=Rhea:RHEA:56364, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:75730, ChEBI:CHEBI:140330;
CC Evidence={ECO:0000269|PubMed:5365804};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=daunorubicin + H(+) + NADPH + O2 = doxorubicin + H2O +
CC NADP(+); Xref=Rhea:RHEA:15717, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:64677, ChEBI:CHEBI:64816; EC=1.14.13.181;
CC Evidence={ECO:0000269|PubMed:5365804};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000250};
CC -!- PATHWAY: Antibiotic biosynthesis; daunorubicin biosynthesis.
CC -!- PATHWAY: Antibiotic biosynthesis; carminomycin biosynthesis.
CC -!- PATHWAY: Antibiotic biosynthesis; doxorubicin biosynthesis.
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- MISCELLANEOUS: S.peucetius subsp. caesius ATCC 27952, a mutant strain
CC derived from S.peucetius ATCC 29050, is the only organism reported to
CC produce doxorubicin in vivo (PubMed:5365804).
CC {ECO:0000305|PubMed:5365804}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AF403708; AAK95626.1; -; Genomic_DNA.
DR AlphaFoldDB; Q93MI2; -.
DR SMR; Q93MI2; -.
DR UniPathway; UPA00054; -.
DR UniPathway; UPA01040; -.
DR UniPathway; UPA01041; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0016709; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen; IDA:UniProtKB.
DR GO; GO:1901771; P:daunorubicin biosynthetic process; IDA:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IDA:UniProtKB.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002397; Cyt_P450_B.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00359; BP450.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Antibiotic biosynthesis; Cytoplasm; Heme; Iron; Metal-binding;
KW Monooxygenase; NADP; Oxidoreductase.
FT CHAIN 1..420
FT /note="Cytochrome P-450 monooxygenase DoxA"
FT /id="PRO_0000425685"
FT BINDING 367
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250"
SQ SEQUENCE 420 AA; 45646 MW; 2083C9FE9BA802C6 CRC64;
MSGEAPRVAV DPFACPMMTM QRKPEVHDAF REAGPVVEVN APAGGPAWFI TDDALSRYVL
ADPRLVKDPD LAPAAWRGVV DGLDIPVPEL RPFTLIAVDG EAHRRLHRIH APAFNPRRLA
ERTDRIAAIA GRLLTELADA SGRSGEPAEL IGGFAYHFPL LVICELLGVP VTVPMAREAV
SVLKALASAA QSGGGDGTDP AGGVPDTSAL ESLLLEAVHS ARRNDTPTMT RVLYEHTQAE
FGSVSDNQLV YMITGIIFAG HERTGSFLGF LLAEVLAGRL AADADEDAVS RFVEEAVRYH
PPVPYTLWRF AATEVTIGGV RLPPGAPVLV DIEGTNTDGR HHDAPHAFHP DRPSWRRLTF
GDGPHYCIGE QLAQLESRTM IGVLRSRFPE ARLAVPYDEL RWCRNGAQTA RLTELPVWLR
