AZPA5_ASPTN
ID AZPA5_ASPTN Reviewed; 231 AA.
AC Q0CRP8;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 25-MAY-2022, entry version 37.
DE RecName: Full=Azasperpyranone A biosynthesis cluster A protein ATEG_03636 {ECO:0000303|PubMed:31908094};
DE Flags: Precursor;
GN ORFNames=ATEG_03636;
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: Part of the cluster A that mediates the biosynthesis of
CC azasperpyranones, members of the azaphilone family that exhibit anti-
CC cancer activities (PubMed:31908094). Azasperpyranones are synthesized
CC by 2 clusters, A and B (PubMed:31908094). Cluster A is responsible for
CC the production of the polyhydric phenol moiety while the azaphilonoid
CC scaffold is produced by the cluster B (PubMed:31908094). The non-
CC reducing polyketide synthase ATEG_03629 produces 5-methyl orsellinic
CC acid, which is then reduced to 5-methyl orsellinic aldehyde by the
CC NRPS-like protein ATEG_03630 (PubMed:24412543). 5-methyl orsellinic
CC aldehyde is then first hydroxylated by the FAD-dependent monooxygenase
CC ATEG_03635 and subsequently hydroxylated by the cytochrome P450
CC monooxygenase ATEG_03631 to produce the unstable polyhydric phenol
CC precursor of azasperpyranones (PubMed:31908094). On the other hand, the
CC polyketide 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 -!- 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}.
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DR EMBL; CH476598; EAU35438.1; -; Genomic_DNA.
DR RefSeq; XP_001212814.1; XM_001212814.1.
DR AlphaFoldDB; Q0CRP8; -.
DR EnsemblFungi; EAU35438; EAU35438; ATEG_03636.
DR GeneID; 4318797; -.
DR VEuPathDB; FungiDB:ATEG_03636; -.
DR eggNOG; ENOG502T9Z1; Eukaryota.
DR HOGENOM; CLU_108995_0_0_1; -.
DR OMA; GFHESAM; -.
DR OrthoDB; 1821563at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
PE 1: Evidence at protein level;
KW Glycoprotein; Reference proteome; Signal.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..231
FT /note="Azasperpyranone A biosynthesis cluster A protein
FT ATEG_03636"
FT /id="PRO_5004170540"
FT CARBOHYD 44
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 95
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 174
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 203
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 231 AA; 24739 MW; 122330B0E93C91F4 CRC64;
MQLLTIVWTS LAAGIMATAT PTSLPLCSMV DRPCKCPPGT TFKNLTTYGV IGAPARDVQD
IMGSSAVFDL QFQGGLVPSS TKGKDNVPGA VRSFNFSGPA GYYVISEQVC LRLRMNSGHV
ADVYKLTKWK TSPDGSFNQQ YQQSPKPPVV QVPGAGAYHG GWTSIVGQQT VVRNETAIAW
KNWRCETGET FPSATSHEGG ITNTSAVLEK QGKLTGVSIA AFTIFNEVRD D
