ADRA_PENRO
ID ADRA_PENRO Reviewed; 508 AA.
AC A0A1Y0BRF2;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2017, sequence version 1.
DT 03-AUG-2022, entry version 11.
DE RecName: Full=Cytochrome P450 monooxygenase adrA {ECO:0000303|PubMed:28529508};
DE EC=1.-.-.- {ECO:0000305|PubMed:28529508};
DE AltName: Full=Andrastin A biosynthesis cluster protein A {ECO:0000303|PubMed:28529508};
GN Name=adrA {ECO:0000303|PubMed:28529508};
OS Penicillium roqueforti.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=5082;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, FUNCTION, AND DISRUPTION
RP PHENOTYPE.
RC STRAIN=CECT 2905;
RX PubMed=28529508; DOI=10.3389/fmicb.2017.00813;
RA Rojas-Aedo J.F., Gil-Duran C., Del-Cid A., Valdes N., Alamos P., Vaca I.,
RA Garcia-Rico R.O., Levican G., Tello M., Chavez R.;
RT "The biosynthetic gene cluster for andrastin A in Penicillium roqueforti.";
RL Front. Microbiol. 8:813-813(2017).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of andrastins, meroterpenoid compounds that
CC exhibit inhibitory activity against ras farnesyltransferase, suggesting
CC that they could be promising leads for antitumor agents
CC (PubMed:28529508). The first step of the pathway is the synthesis of
CC 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase adrD via
CC condensation of one acetyl-CoA starter unit with 3 malonyl-CoA units
CC and 2 methylations (By similarity). DMAO is then converted to farnesyl-
CC DMAO by the prenyltransferase adrG (By similarity). The
CC methyltransferase adrK catalyzes the methylation of the carboxyl group
CC of farnesyl-DMAO to farnesyl-DMAO methyl ester which is further
CC converted to epoxyfarnesyl-DMAO methyl ester by the FAD-dependent
CC monooxygenase adrH (By similarity). The terpene cyclase adrI then
CC catalyzes the carbon skeletal rearrangement to generate the andrastin
CC E, the first compound in the pathway having the andrastin scaffold,
CC with the tetracyclic ring system (By similarity). The post-cyclization
CC tailoring enzymes adrF, adrE, adrJ, and adrA, are involved in the
CC conversion of andrastin E into andrastin A. The short chain
CC dehydrogenase adrF is responsible for the oxidation of the C-3 a
CC hydroxyl group of andrastin E to yield the corresponding ketone,
CC andrastin D. The ketoreductase adrE stereoselectively reduces the
CC carbonyl moiety to reverse the stereochemistry of the C-3 position to
CC yield andrastin F. The acetyltransferase adrJ is the acetyltransferase
CC that attaches the acetyl group to the C-3 hydroxyl group of andrastin F
CC to yield andrastin C. Finally, the cytochrome P450 monooxygenase adrA
CC catalyzes two sequential oxidation reactions of the C-23 methyl group,
CC to generate the corresponding alcohol andrastin B, and aldehyde
CC andrastin A (By similarity). {ECO:0000250|UniProtKB:B6HUQ4,
CC ECO:0000269|PubMed:28529508}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:28529508}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Drastically reduces the production of andrastin
CC A. {ECO:0000269|PubMed:28529508}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; KY349137; ART41207.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A1Y0BRF2; -.
DR SMR; A0A1Y0BRF2; -.
DR UniPathway; UPA00213; -.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 3: Inferred from homology;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..508
FT /note="Cytochrome P450 monooxygenase adrA"
FT /id="PRO_0000446456"
FT TRANSMEM 12..32
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 449
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|UniProtKB:P04798"
FT CARBOHYD 82
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 206
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 508 AA; 57182 MW; BCD330015128BD86 CRC64;
MAVDKLPLLA KLEPVSLIGL VLLSGLFFLL TATRKSDLPL VNGKRPFEFG IAKARQRYLK
NAHSLITAGL EKAGAFRIVT ENGTRTILSP KYADDIRSHR DLSLSAALVK EHHVNIAGFD
AVKVTVTSDI IQDTVRTKLT QNLLNITEPM SEEATILLKA QWTDSTEWHD VALRPKTLGI
VAQLSSRVFL GDKVCRNPDW LRLTVNYTID SLMAAAELRL WPEMLRPIAA KFLPKCKKIR
KQLEEARNII QPVIDERRLA QQAAIKQGKP QERYHDAIQW LAENTKDRTF EPAAMQLALS
TAAIHTTTDL LTQTILDLCG REELVQELRE EIISVFKDGS WDKTTMYKLK LMDSVIKESQ
RVKPMAIAKM ARCAEEDVKL SDGTIIPRGE IILVSCSKMW DANVYPDPNT FDPHRFLKLR
QQGSDQESFA QLVSPSPEHM GFGFGKHACP GRFFAAAELK VALCHIIMKY DFKVAEGCNP
QVLKSGMRLA ADPFARIAIR RRQEEISF
