AZPB3_ASPTN
ID AZPB3_ASPTN Reviewed; 481 AA.
AC Q0CF74;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 25-MAY-2022, entry version 59.
DE RecName: Full=FAD-linked oxidoreductase ATEG_07660 {ECO:0000303|PubMed:31908094};
DE EC=1.-.-.- {ECO:0000305|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster B protein ATEG_07660 {ECO:0000303|PubMed:31908094};
DE Flags: Precursor;
GN ORFNames=ATEG_07660;
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, AND DISRUPTION PHENOTYPE.
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-linked oxidoreductase; 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 -!- 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: Does not affect the production of azasperpyranone
CC A. {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 oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; CH476604; EAU31922.1; -; Genomic_DNA.
DR RefSeq; XP_001216281.1; XM_001216281.1.
DR AlphaFoldDB; Q0CF74; -.
DR SMR; Q0CF74; -.
DR STRING; 33178.CADATEAP00001524; -.
DR EnsemblFungi; EAU31922; EAU31922; ATEG_07660.
DR GeneID; 4323013; -.
DR VEuPathDB; FungiDB:ATEG_07660; -.
DR eggNOG; ENOG502SJ3M; Eukaryota.
DR HOGENOM; CLU_018354_0_1_1; -.
DR OMA; WVSPATE; -.
DR OrthoDB; 350817at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 1.
DR InterPro; IPR012951; BBE.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF08031; BBE; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Oxidoreductase; Reference proteome;
KW Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..481
FT /note="FAD-linked oxidoreductase ATEG_07660"
FT /id="PRO_5004170193"
FT DOMAIN 58..231
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 276
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 280
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 316
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 380
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 481 AA; 52402 MW; 036E414924FC9581 CRC64;
MLRQLYQSLA LVAAVHATGI FANGVDIESL FGPYLSPGTE IAEPTDADFS TVASPRWSEW
KPPTWTGAIK PKTERDLQKI VRIAAAHNLP FMATNGGHGT SLIYGTVKGI DVNLENFNSV
KIDIEKNTLT VGGGTKLGDI TEPLYNAGKA IPRGNSPCVG VIGATIGGGI GFNTGLFGLG
VDALVEVRLV TATGDIVTVS EKRHPDLLWA IRGAGANFGI ITEATFRMSD QPNNGDAVIG
SFVYPAEGAL AVFEELQSLD YVLPADLGVQ LSIAYNRTIN ASELTVDMKH FGPWDTFVPH
WNTAERLKPI ARTIKNVTLV ELYAGLDGPC QSGVYVSGGT TGLGRTDPQT MKEVMDEMTA
FYEAHPGFLG QTLFQRYANN NTLKTPLSTA VYPWRDTKNF WLHENIYTDP ALEQPSIDLL
LSLRKKLQAT SGFDEPHIYV NYAFGDEGPA AWWGADNLPR LRRLKRRWDP KGLFGRGTPI
F
