AZPA4_ASPTN
ID AZPA4_ASPTN Reviewed; 705 AA.
AC Q0CRP9;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 69.
DE RecName: Full=FAD-dependent monooxygenase ATEG_03635 {ECO:0000303|PubMed:31908094};
DE EC=1.-.-.- {ECO:0000269|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster A protein ATEG_03635 {ECO:0000303|PubMed:31908094};
GN ORFNames=ATEG_03635;
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: FAD-dependent 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=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q6SSJ6};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:31908094}.
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 PheA/TfdB FAD monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; CH476598; EAU35437.1; -; Genomic_DNA.
DR RefSeq; XP_001212813.1; XM_001212813.1.
DR AlphaFoldDB; Q0CRP9; -.
DR SMR; Q0CRP9; -.
DR STRING; 33178.CADATEAP00008215; -.
DR EnsemblFungi; EAU35437; EAU35437; ATEG_03635.
DR GeneID; 4318796; -.
DR VEuPathDB; FungiDB:ATEG_03635; -.
DR eggNOG; KOG3855; Eukaryota.
DR HOGENOM; CLU_009665_9_2_1; -.
DR OMA; FASAMSW; -.
DR OrthoDB; 366744at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
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; 3.40.30.20; -; 1.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR012941; Phe_hydrox_C_dim_dom.
DR InterPro; IPR038220; PHOX_C_sf.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR Pfam; PF07976; Phe_hydrox_dim; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
DR SUPFAM; SSF52833; SSF52833; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Monooxygenase; Oxidoreductase; Reference proteome.
FT CHAIN 1..705
FT /note="FAD-dependent monooxygenase ATEG_03635"
FT /id="PRO_0000450088"
FT BINDING 86..115
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
FT BINDING 208
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
FT BINDING 308..310
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
FT BINDING 408
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q6SSJ6"
SQ SEQUENCE 705 AA; 78734 MW; 2E0BF0AA5FBB8C8B CRC64;
MASTLPPQTW EAGYARPADQ ASWEAETNYV AESGERAHWM LPVHTEPPTS TIGNGLGLTH
LRTWPSIYDG TATGKPEWFK PSKEVDVLIC GAGPFGLELG LILARQGISF RIVDKANAPC
LSGRADGVHP RALEQLHAWG LAHEVSEEGP ILNSTVLFRN GVKLFHGFSS TCDSRYKGIH
IITQGQMERI YIRDLLRHQI VVERGTTVQH FNVQSTSQDH PVRATLKNVA TGEEEVVRAR
YLIGADGAAS SIREQLGVEF DGITTDIYWA IMDCRFKTDY PHILGFNIII SAEHGGSIVI
PREDGYTRFY TQINGEKARK LQANRQARRN ASTVGETRID DHGITPDEVL EQLNKIIAPH
KVEFASPMSW FSVWRVSERV ARHFSSPDLR VHLGGDAAVL GAFGLNSSIY DAANLGWKLG
LVLRKHAEPS ILTTYDKERR LFANRVIRCS GAYLRFICNS SLPLAALRDL GEHLESHDEN
LPLLDGSTEA DREFLYTFFK RHAMFLLGVE WPIVNSAICP ADTKVRASSL RNGVRAPNPR
VCLATDYTAY LYDKMMGVGR FHLLLFGSDL QGPVRQRLAV LAGELRKREG FYERFGGREM
FNLILVVKTL SHQTAELLEG DLAPLKDHAT TVYDDRAPDD DAHYWYGVNH ARGALVVVRP
DLAVGVSVWP EEIGKLNKYF ASFLLECEET LPTKKSLLAR LWDAL
