ADRA_PENRW
ID ADRA_PENRW Reviewed; 512 AA.
AC B6HUQ4;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 1.
DT 03-AUG-2022, entry version 72.
DE RecName: Full=Cytochrome P450 monooxygenase adrA {ECO:0000303|Ref.2};
DE EC=1.-.-.- {ECO:0000269|Ref.2};
DE AltName: Full=Andrastin A biosynthesis cluster protein A {ECO:0000303|Ref.2};
GN Name=adrA {ECO:0000303|Ref.2}; ORFNames=Pc22g22820;
OS Penicillium rubens (strain ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin
OS 54-1255) (Penicillium chrysogenum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium;
OC Penicillium chrysogenum species complex.
OX NCBI_TaxID=500485;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 28089 / DSM 1075 / NRRL 1951 / Wisconsin 54-1255;
RX PubMed=18820685; DOI=10.1038/nbt.1498;
RA van den Berg M.A., Albang R., Albermann K., Badger J.H., Daran J.-M.,
RA Driessen A.J.M., Garcia-Estrada C., Fedorova N.D., Harris D.M.,
RA Heijne W.H.M., Joardar V.S., Kiel J.A.K.W., Kovalchuk A., Martin J.F.,
RA Nierman W.C., Nijland J.G., Pronk J.T., Roubos J.A., van der Klei I.J.,
RA van Peij N.N.M.E., Veenhuis M., von Doehren H., Wagner C., Wortman J.R.,
RA Bovenberg R.A.L.;
RT "Genome sequencing and analysis of the filamentous fungus Penicillium
RT chrysogenum.";
RL Nat. Biotechnol. 26:1161-1168(2008).
RN [2]
RP IDENTIFICATION, FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX DOI=10.1016/j.tet.2013.07.029;
RA Matsuda Y., Awakawa T., Abe I.;
RT "Reconstituted biosynthesis of fungal meroterpenoid andrastin A.";
RL Tetrahedron 69:8199-8204(2013).
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 (Ref.2). The
CC first step of the pathway is the synthesis of 3,5-dimethylorsellinic
CC acid (DMOA) by the polyketide synthase adrD via condensation of one
CC acetyl-CoA starter unit with 3 malonyl-CoA units and 2 methylations
CC (Ref.2). DMAO is then converted to farnesyl-DMAO by the
CC prenyltransferase adrG (Ref.2). The methyltransferase adrK catalyzes
CC the methylation of the carboxyl group of farnesyl-DMAO to farnesyl-DMAO
CC methyl ester which is further converted to epoxyfarnesyl-DMAO methyl
CC ester by the FAD-dependent monooxygenase adrH (Ref.2). The terpene
CC cyclase adrI then catalyzes the carbon skeletal rearrangement to
CC generate the andrastin E, the first compound in the pathway having the
CC andrastin scaffold, with the tetracyclic ring system (Ref.2). The post-
CC cyclization tailoring enzymes adrF, adrE, adrJ, and adrA, are involved
CC in the 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 (Ref.2). {ECO:0000269|Ref.2}.
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|Ref.2}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AM920437; CAP99570.1; -; Genomic_DNA.
DR RefSeq; XP_002566176.1; XM_002566130.1.
DR AlphaFoldDB; B6HUQ4; -.
DR SMR; B6HUQ4; -.
DR EnsemblFungi; CAP99570; CAP99570; PCH_Pc22g22820.
DR GeneID; 8309008; -.
DR KEGG; pcs:Pc22g22820; -.
DR VEuPathDB; FungiDB:PCH_Pc22g22820; -.
DR eggNOG; KOG0158; Eukaryota.
DR HOGENOM; CLU_022195_0_3_1; -.
DR OMA; EHMGFGF; -.
DR OrthoDB; 572303at2759; -.
DR BioCyc; PCHR:PC22G22820-MON; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000000724; Contig Pc00c22.
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 SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..512
FT /note="Cytochrome P450 monooxygenase adrA"
FT /id="PRO_0000446455"
FT TRANSMEM 12..32
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 453
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 86
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 149
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 210
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 512 AA; 57501 MW; FE7BFC2DF734DA24 CRC64;
MAVDKLPLLA KFEPVSLVGL VLLSGLFLLL TASRKSDLPL VNGKRPFEFG IAKARQRYLK
NAHNLITAGL AKVCNSAGAF RIVTENGTRT ILSPNYADDI RSHRDLSLSA ALVKEHHVNI
AGFDAVKVTV TSDIIQDTVR TKLTQNLLNI TEPMSEEATI LLKEQWTDNT DWHDVALRPK
TLGIVAQLSS RVFLGDKVCR NPDWLRITVN YTIDSLMAAA ELRLWPEMLR PLAARFLPKC
KKIRKQLEEA RDIIQPVIDE RRLAQQEAIK QGKPQERYHD AIQWLAENTK DRSFEPAAMQ
LALSTAAIHT TTDLLGQTVL DLCGRDELIQ ELREEIISVF KDGSWDKSTM YKLKLMDSVI
KESQRVKPMA IAKMARCAEE DVKLSDGTII PKGEIILVSC SKMWDANVYP DPNTFDPHRF
LKMRQPGSDQ ESFAQLVSPS PEHMGFGFGK HACPGRFFAA AELKVALCHI IMKYDFKVAD
GCNPQVLKSG MRLAADPFAK IAIRRRQEEV TF
