ID   AZPA3_ASPTN             Reviewed;         492 AA.
AC   Q0CRQ3;
DT   17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT   17-JUN-2020, sequence version 2.
DT   03-AUG-2022, entry version 59.
DE   RecName: Full=Cytochrome P450 monooxygenase ATEG_03631 {ECO:0000303|PubMed:31908094};
DE            EC=1.-.-.- {ECO:0000269|PubMed:31908094};
DE   AltName: Full=Azasperpyranone A biosynthesis cluster A protein ATEG_03631 {ECO:0000303|PubMed:31908094};
GN   ORFNames=ATEG_03631;
OS   Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC   Aspergillus subgen. Circumdati.
OX   NCBI_TaxID=341663;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=NIH 2624 / FGSC A1156;
RA   Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA   Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA   Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA   Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA   Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA   Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA   Nierman W.C., Milne T., Madden K.;
RT   "Annotation of the Aspergillus terreus NIH2624 genome.";
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   FUNCTION.
RX   PubMed=24412543; DOI=10.1016/j.chembiol.2013.12.005;
RA   Wang M., Beissner M., Zhao H.;
RT   "Aryl-aldehyde formation in fungal polyketides: discovery and
RT   characterization of a distinct biosynthetic mechanism.";
RL   Chem. Biol. 21:257-263(2014).
RN   [3]
RP   FUNCTION.
RX   PubMed=23621425; DOI=10.1021/ja401945a;
RA   Chiang Y.M., Oakley C.E., Ahuja M., Entwistle R., Schultz A., Chang S.L.,
RA   Sung C.T., Wang C.C., Oakley B.R.;
RT   "An efficient system for heterologous expression of secondary metabolite
RT   genes in Aspergillus nidulans.";
RL   J. Am. Chem. Soc. 135:7720-7731(2013).
RN   [4]
RP   FUNCTION, INDUCTION, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, PATHWAY, AND
RP   BIOTECHNOLOGY.
RX   PubMed=31908094; DOI=10.1002/anie.201915514;
RA   Huang X., Zhang W., Tang S., Wei S., Lu X.;
RT   "Collaborative biosynthesis of a class of bioactive azaphilones by two
RT   separate gene clusters containing four PKS/NRPSs with transcriptional
RT   cosstalk in fungi.";
RL   Angew. Chem. Int. Ed. 59:4349-4353(2020).
CC   -!- FUNCTION: Cytochrome P450 monooxygenase; part of the cluster A that
CC       mediates the biosynthesis of azasperpyranones, members of the
CC       azaphilone family that exhibit anti-cancer activities
CC       (PubMed:31908094). Azasperpyranones are synthesized by 2 clusters, A
CC       and B (PubMed:31908094). Cluster A is responsible for the production of
CC       the polyhydric phenol moiety while the azaphilonoid scaffold is
CC       produced by the cluster B (PubMed:31908094). The non-reducing
CC       polyketide synthase ATEG_03629 produces 5-methyl orsellinic acid, which
CC       is then reduced to 5-methyl orsellinic aldehyde by the NRPS-like
CC       protein ATEG_03630 (PubMed:24412543). 5-methyl orsellinic aldehyde is
CC       then first hydroxylated by the FAD-dependent monooxygenase ATEG_03635
CC       and subsequently hydroxylated by the cytochrome P450 monooxygenase
CC       ATEG_03631 to produce the unstable polyhydric phenol precursor of
CC       azasperpyranones (PubMed:31908094). On the other hand, the polyketide
CC       synthase ATEG_07659 is responsible for producing the 3,5-
CC       dimethyloctadienone moiety from acetyl-CoA, three malonyl-CoA, and two
CC       S-adenosyl methionines (SAM) (Probable). The 3,5-dimethyloctadienone
CC       moiety is then loaded onto the SAT domain of ATEG_07661 and extended
CC       with four malonyl-CoA and one SAM, which leads to the formation of 2,4-
CC       dihydroxy-6-(5,7-dimethyl-2-oxo-trans-3-trans-5-nonadienyl)-3-
CC       methylbenzaldehyde (compound 8) after reductive release and aldol
CC       condensation (Probable). The FAD-dependent monooxygenase ATEG_07662 is
CC       the next enzyme in the biosynthesis sequence and hydroxylates the side
CC       chain at the benzylic position of compound 8 (Probable). In Aspergillus
CC       nidulans, afoF, the ortholog of the FAD-dependent oxygenase ATEG_07660,
CC       is the key enzyme for the biosynthesis of asperfuranone by catalyzing
CC       the hydroxylation at C-8 of to prevent the formation of a six-membered
CC       ring hemiacetal intermediate and thus facilitatings the formation of a
CC       five-membered ring to produce asperfuranone (Probable). In Aspergillus
CC       terreus, ATEG_07660 is probably not functional, which leads to the
CC       formation of the six-membered ring hemiacetal intermediate
CC       presperpyranone instead of asperfuranone (Probable). Finally,
CC       ATEG_03636 is involved in the condensation of the polyhydric phenol
CC       moiety produced by cluster A and the perasperpyranone precursor
CC       produced by cluster B, to yield azasperpyranone A (Probable). Further
CC       modifications of azasperpyranone A result in the production of
CC       derivatives, including azasperpyranone B to F (PubMed:31908094).
CC       {ECO:0000269|PubMed:24412543, ECO:0000269|PubMed:31908094,
CC       ECO:0000305|PubMed:31908094}.
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:31908094}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
CC   -!- INDUCTION: Expression is induced by the azasperpyranone cluster A-
CC       specific transcription factor ATEG_03638 which is itself regulated by
CC       the azasperpyranone transcriptional regulator ATEG_07667.
CC       {ECO:0000269|PubMed:31908094}.
CC   -!- DISRUPTION PHENOTYPE: Abolishes the production of azasperpyranone A.
CC       {ECO:0000269|PubMed:31908094}.
CC   -!- BIOTECHNOLOGY: Azasperpyranones display potential anti-cancer
CC       activities (PubMed:31908094). Azasperpyranones A, C, D, and F exhibit
CC       potent growth-inhibitory activity against the A549, HepG2, HCT-116, and
CC       HL-60 cell lines, with IC(50) values of 2.39-14.42 mm, respectively
CC       (PubMed:31908094). Moreover, azasperpyranone D significantly inhibits
CC       HCT-116 xenograft tumor growth in BALB/c-nu mice (PubMed:31908094). In
CC       addition, azasperpyranones A and C can bind with four kinds of
CC       therapeutic targets for cancer, eEF2K, FGFR, survivin, and TNF-a
CC       (PubMed:31908094). {ECO:0000269|PubMed:31908094}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=EAU35433.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; CH476598; EAU35433.1; ALT_SEQ; Genomic_DNA.
DR   RefSeq; XP_001212809.1; XM_001212809.1.
DR   AlphaFoldDB; Q0CRQ3; -.
DR   SMR; Q0CRQ3; -.
DR   EnsemblFungi; EAU35433; EAU35433; ATEG_03631.
DR   GeneID; 4318787; -.
DR   eggNOG; KOG0156; Eukaryota.
DR   HOGENOM; CLU_001570_14_0_1; -.
DR   OrthoDB; 467733at2759; -.
DR   Proteomes; UP000007963; Unassembled WGS sequence.
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   Gene3D; 1.10.630.10; -; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002401; Cyt_P450_E_grp-I.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; SSF48264; 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..492
FT                   /note="Cytochrome P450 monooxygenase ATEG_03631"
FT                   /id="PRO_0000450087"
FT   TRANSMEM        10..30
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         457
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        309
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ   SEQUENCE   492 AA;  56140 MW;  317A904D4F5D98F0 CRC64;
     MALLEDIINF ATLNPMVVVA IPVFLFVISL LRSYLRLAHI PGPFAAGWTN LPRFSWVLSF
     KAHDIHTALH RKYGPLVRFG PNMVSVGDPK EVGHIYGFTD PWMKSDFYHA LLMKPRGKPI
     PGIFAAQDEN IHRALKKPIS SAYSMSTLLS FEPYVDSTMR VFCEQLESRF IENKKPLDFG
     KWLQMFAFDV IGELTFSRRL GFLESGEDIN HVMANIWETF KKTSLVTQMP WLDKLWTNNP
     IQRWRRGGGA SPGAAFAMAR VEERRELQRT TNKNDWHFNT RDFLSRFMEA EAKDPSIPPY
     ALAAWASSNI TAGSDTTGIF LRTIFYQLLT HPETLRKLRE ELDQAAAAGN LDDLASWKQT
     RELPYLDAVI KEGGRIHPPF GLPYERVVPA QGATICGKFL PGGTLVGMSA WVVHRNKELY
     GEDCDEWNPD RWLKCDTEKR RKMENALLTF GAGHRTCMGK HIAYLEMYKV VPTLLRKYDV
     SRLLCFLVSR TG