AACUC_ASPA1
ID AACUC_ASPA1 Reviewed; 514 AA.
AC A0A1L9WLG2;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2017, sequence version 1.
DT 03-AUG-2022, entry version 19.
DE RecName: Full=FAD-dependent monooxygenase AacuC {ECO:0000303|PubMed:30996871};
DE Short=FMO AacuC {ECO:0000303|PubMed:30996871};
DE EC=1.-.-.- {ECO:0000305|PubMed:30996871};
DE AltName: Full=Secalonic acid biosynthesis cluster protein C {ECO:0000303|PubMed:30996871};
GN Name=AacuC {ECO:0000303|PubMed:30996871}; ORFNames=ASPACDRAFT_63291;
OS Aspergillus aculeatus (strain ATCC 16872 / CBS 172.66 / WB 5094).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=690307;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 16872 / CBS 172.66 / WB 5094;
RX PubMed=28196534; DOI=10.1186/s13059-017-1151-0;
RA de Vries R.P., Riley R., Wiebenga A., Aguilar-Osorio G., Amillis S.,
RA Uchima C.A., Anderluh G., Asadollahi M., Askin M., Barry K., Battaglia E.,
RA Bayram O., Benocci T., Braus-Stromeyer S.A., Caldana C., Canovas D.,
RA Cerqueira G.C., Chen F., Chen W., Choi C., Clum A., Dos Santos R.A.,
RA Damasio A.R., Diallinas G., Emri T., Fekete E., Flipphi M., Freyberg S.,
RA Gallo A., Gournas C., Habgood R., Hainaut M., Harispe M.L., Henrissat B.,
RA Hilden K.S., Hope R., Hossain A., Karabika E., Karaffa L., Karanyi Z.,
RA Krasevec N., Kuo A., Kusch H., LaButti K., Lagendijk E.L., Lapidus A.,
RA Levasseur A., Lindquist E., Lipzen A., Logrieco A.F., MacCabe A.,
RA Maekelae M.R., Malavazi I., Melin P., Meyer V., Mielnichuk N., Miskei M.,
RA Molnar A.P., Mule G., Ngan C.Y., Orejas M., Orosz E., Ouedraogo J.P.,
RA Overkamp K.M., Park H.-S., Perrone G., Piumi F., Punt P.J., Ram A.F.,
RA Ramon A., Rauscher S., Record E., Riano-Pachon D.M., Robert V., Roehrig J.,
RA Ruller R., Salamov A., Salih N.S., Samson R.A., Sandor E., Sanguinetti M.,
RA Schuetze T., Sepcic K., Shelest E., Sherlock G., Sophianopoulou V.,
RA Squina F.M., Sun H., Susca A., Todd R.B., Tsang A., Unkles S.E.,
RA van de Wiele N., van Rossen-Uffink D., Oliveira J.V., Vesth T.C.,
RA Visser J., Yu J.-H., Zhou M., Andersen M.R., Archer D.B., Baker S.E.,
RA Benoit I., Brakhage A.A., Braus G.H., Fischer R., Frisvad J.C.,
RA Goldman G.H., Houbraken J., Oakley B., Pocsi I., Scazzocchio C.,
RA Seiboth B., vanKuyk P.A., Wortman J., Dyer P.S., Grigoriev I.V.;
RT "Comparative genomics reveals high biological diversity and specific
RT adaptations in the industrially and medically important fungal genus
RT Aspergillus.";
RL Genome Biol. 18:RESEARCH28.1-RESEARCH28.45(2017).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=28253713; DOI=10.4149/neo_2017_304;
RA Gao X., Sun H.L., Liu D.S., Zhang J.R., Zhang J., Yan M.M., Pan X.H.;
RT "Secalonic acid- F inhibited cell growth more effectively than 5-
RT fluorouracil on hepatocellular carcinoma in vitro and in vivo.";
RL Neoplasma 64:344-350(2017).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=29248948; DOI=10.1007/s00284-017-1411-y;
RA Yodsing N., Lekphrom R., Sangsopha W., Aimi T., Boonlue S.;
RT "Secondary Metabolites and Their Biological Activity from Aspergillus
RT aculeatus KKU-CT2.";
RL Curr. Microbiol. 75:513-518(2018).
RN [4]
RP IDENTIFICATION, AND FUNCTION.
RX PubMed=30996871; DOI=10.1039/c8sc05126g;
RA Greco C., de Mattos-Shipley K., Bailey A.M., Mulholland N.P., Vincent J.L.,
RA Willis C.L., Cox R.J., Simpson T.J.;
RT "Structure revision of cryptosporioptides and determination of the genetic
RT basis for dimeric xanthone biosynthesis in fungi.";
RL Chem. Sci. 10:2930-2939(2019).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=30678274; DOI=10.3390/molecules24030393;
RA Xie L., Li M., Liu D., Wang X., Wang P., Dai H., Yang W., Liu W., Hu X.,
RA Zhao M.;
RT "Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of
RT Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/beta-catenin
RT Signaling Pathway.";
RL Molecules 24:0-0(2019).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=33015446; DOI=10.1021/acsomega.0c02505;
RA Farooq S., Qayum A., Nalli Y., Lauro G., Chini M.G., Bifulco G.,
RA Chaubey A., Singh S.K., Riyaz-Ul-Hassan S., Ali A.;
RT "Discovery of a Secalonic Acid Derivative from Aspergillus aculeatus, an
RT Endophyte of Rosa damascena Mill., Triggers Apoptosis in MDA-MB-231 Triple
RT Negative Breast Cancer Cells.";
RL ACS Omega 5:24296-24310(2020).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=33891392; DOI=10.1021/acs.jnatprod.1c00022;
RA Wei X., Chen X., Chen L., Yan D., Wang W.G., Matsuda Y.;
RT "Heterologous biosynthesis of tetrahydroxanthone dimers: determination of
RT key factors for selective or divergent synthesis.";
RL J. Nat. Prod. 84:1544-1549(2021).
CC -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of the tetrahydroxanthone dimer secalonic
CC acid D (PubMed:30996871, PubMed:33891392). The pathway begins with the
CC synthesis of atrochrysone thioester by the polyketide synthase AacuL
CC (Probable). The atrochrysone carboxyl ACP thioesterase AacuM then
CC breaks the thioester bond and releases the atrochrysone carboxylic acid
CC from AacuL (Probable). Atrochrysone carboxylic acid is decarboxylated
CC by the decarboxylase AacuI, and oxidized by the anthrone oxygenase
CC AacuG to yield emodin (Probable). Emodin is then reduced to emodin
CC hydroquinone by a yet unidentified oxidoreductase (Probable). A-ring
CC reduction by the short chain dehydrogenase AacuN, dehydration by the
CC scytalone dehydratase-like protein AacuK and probable spontaneous re-
CC oxidation, results in overall deoxygenation to chrysophanol
CC (PubMed:33891392). Baeyer-Villiger oxidation by the Baeyer-Villiger
CC monooxygenase (BVMO) AacuH then yields monodictyphenone
CC (PubMed:33891392). Monodictyphenone is transformed into compounds with
CC the tetrahydroxanthone skeleton via methylesterification by the
CC methyltransferase AacuQ, followed by the action of the flavin-dependent
CC monooxygenase AacuC, the isomerase AacuP, and the short chain
CC dehydrogenase/reductase AacuF or AacuD (PubMed:33891392). AacuF and
CC AacuD should accept the same compound as a substrate but perform the
CC ketoreduction with a different stereoselectivity, thus yielding
CC blennolides B and A, respectively (PubMed:33891392). In the final step
CC of the biosynthesis, the cytochrome P450 monooxygenase AacuE accepts
CC blennolide B and/or blennolide A to conduct the dimerization reaction
CC to furnish the tetrahydroxanthone dimers, secalonic acids D, B, and F
CC (PubMed:33891392). {ECO:0000269|PubMed:30996871,
CC ECO:0000269|PubMed:33891392, ECO:0000305|PubMed:33891392}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:30996871}.
CC -!- BIOTECHNOLOGY: Secalonic acids show unprecedented anticancer activities
CC against various human cancer cells and might be interesting for further
CC derivatization, targeting diseases such as cancer.
CC {ECO:0000269|PubMed:28253713, ECO:0000269|PubMed:29248948,
CC ECO:0000269|PubMed:30678274, ECO:0000269|PubMed:33015446}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; KV878984; OJJ96981.1; -; Genomic_DNA.
DR RefSeq; XP_020053321.1; XM_020203870.1.
DR SMR; A0A1L9WLG2; -.
DR EnsemblFungi; OJJ96981; OJJ96981; ASPACDRAFT_63291.
DR GeneID; 30977684; -.
DR VEuPathDB; FungiDB:ASPACDRAFT_63291; -.
DR OrthoDB; 462247at2759; -.
DR Proteomes; UP000184546; 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; 3.50.50.60; -; 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; Monooxygenase; Oxidoreductase; Reference proteome.
FT CHAIN 1..514
FT /note="FAD-dependent monooxygenase AacuC"
FT /id="PRO_0000453479"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 66..67
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 358
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 368..372
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
SQ SEQUENCE 514 AA; 57078 MW; E6ED4C39F42E3494 CRC64;
MVSNEYLTHG DKDEFDPAKW SSTPGELPPR SPATNLNVLI VGAGPAGLIT ALECWRKGHN
VVRILERSQG PVYTGDIIVI GPSAICTLRH WPEICRELDQ DRSDSVMYYR RHNGELILGP
TTLGYNSPEH LAQRHGLPYV APHQVRRQFY RMLLRQVARI GLQVEYGQRV ERYFEDEAAG
VGGVVTADGS VRAAHLVVAA DAFKTRSDLL IAGRHAPTRS SGMSVYRAAL PTELALRDPA
FQARWGEVVA RGESHHEFWI GPGMHLGLFI SPNFVAYGLS PRDKFLQPGG IEPIESWDPD
VNPQEVLDVL HRIPDWDPAI EGLIRHTPPR ATVHWPLLWR NLRREWTSKA GRVVQVGDAA
HTTVPASISG GTLAIEDAVT LAACLQLACA GGAPGGAPLG ARIYNLLRYQ RVSCVQKMSF
VNSENLGAAD MNEVLKKDPE KVKVRFPKWL FQHDPEAYVY EKYGQAYAHL VLGTDFQNTN
FPPGHDFKMW TIEEIHADIL AGKKVADLLD GDWD
