AZPB4_ASPTN
ID AZPB4_ASPTN Reviewed; 435 AA.
AC Q0CF72;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 65.
DE RecName: Full=FAD-dependent monooxygenase ATEG_07662 {ECO:0000303|PubMed:31908094};
DE EC=1.-.-.- {ECO:0000305|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster B protein ATEG_07662 {ECO:0000303|PubMed:31908094};
GN ORFNames=ATEG_07662;
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, PATHWAY, AND 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: FAD-dependent monooxygenase; part of the cluster B 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=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
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_07666 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 paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; CH476604; EAU31924.1; -; Genomic_DNA.
DR RefSeq; XP_001216283.1; XM_001216283.1.
DR AlphaFoldDB; Q0CF72; -.
DR SMR; Q0CF72; -.
DR STRING; 341663.Q0CF72; -.
DR EnsemblFungi; EAU31924; EAU31924; ATEG_07662.
DR GeneID; 4323015; -.
DR VEuPathDB; FungiDB:ATEG_07662; -.
DR eggNOG; KOG2614; Eukaryota.
DR HOGENOM; CLU_009665_6_3_1; -.
DR OMA; WSCLRSH; -.
DR OrthoDB; 521070at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Membrane; Monooxygenase; Oxidoreductase;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..435
FT /note="FAD-dependent monooxygenase ATEG_07662"
FT /id="PRO_0000450090"
FT TRANSMEM 8..28
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 38..39
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 242..244
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 317
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 327..331
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 191
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 435 AA; 47764 MW; 7229611C666C2BB9 CRC64;
MTVADRAPLD VAIIGGGIIG IMTALGLLHR GFRVTVYERA ASWPEIGAAF AFTGVARQCM
ERLDPRVLES LARVAQRSPH EKVRYWDGFH PRTKEAAQEE SAVLFEILEK HMAYWACIRG
HFLLDMAAQL PDGVVQFGKR LVDYNDDEAN EKVVLCFADG STAESDVVIA CDGIHSATRK
VLLGVDHPAA NASYSRKSMY RAMVPMADAV SALGTEKAHV QIAHLGPDAH VVSFPVNNGQ
VYNVFLFLHD PNEWDHGHTM TVPSSRSEVM DAIQGWGPHI KEIVSCFPET VSKYAIFDQA
DNPLPYYASG RVCLAGDAAH ASSPFHGAGA CMGVEDALVL AELLGLVDAG PVAARQRNIK
AALQTYSSVR IERSQWLVQS SRDMGDLYEW RYPPTGEDGA KCKAEFERRS KVIWDFDVDG
MVAGAKKKYE HSMEA
