AACUL_ASPA1
ID AACUL_ASPA1 Reviewed; 1792 AA.
AC A0A1L9WLD9;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2017, sequence version 1.
DT 03-AUG-2022, entry version 27.
DE RecName: Full=Atrochrysone carboxylic acid synthase AacuL {ECO:0000250|UniProtKB:Q5BH30};
DE Short=ACAS AacuL {ECO:0000250|UniProtKB:Q5BH30};
DE EC=2.3.1.- {ECO:0000250|UniProtKB:Q5BH30};
DE AltName: Full=Non-reducing polyketide synthase AacuL {ECO:0000303|PubMed:30996871};
DE AltName: Full=Secalonic acid biosynthesis cluster protein L {ECO:0000303|PubMed:30996871};
GN Name=AacuL {ECO:0000303|PubMed:30996871}; ORFNames=ASPACDRAFT_33832;
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, 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: Atrochrysone carboxylic acid synthase; part of the gene
CC cluster that mediates the biosynthesis of the tetrahydroxanthone dimer
CC secalonic acid D (PubMed:30996871, PubMed:33891392). The pathway begins
CC with the synthesis of atrochrysone thioester by the polyketide synthase
CC AacuL (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 -!- CATALYTIC ACTIVITY:
CC Reaction=8 H(+) + holo-[ACP] + 8 malonyl-CoA = atrochrysone carboxyl-
CC [ACP] + 8 CO2 + 8 CoA + 2 H2O; Xref=Rhea:RHEA:64232, Rhea:RHEA-
CC COMP:9685, Rhea:RHEA-COMP:16552, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:64479, ChEBI:CHEBI:149712;
CC Evidence={ECO:0000250|UniProtKB:Q5BH30};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64233;
CC Evidence={ECO:0000250|UniProtKB:Q5BH30};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30996871}.
CC -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC serves as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm. {ECO:0000250|UniProtKB:Q5B0D0}.
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 ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; KV878984; OJJ96972.1; -; Genomic_DNA.
DR RefSeq; XP_020053312.1; XM_020199993.1.
DR SMR; A0A1L9WLD9; -.
DR STRING; 690307.A0A1L9WLD9; -.
DR EnsemblFungi; OJJ96972; OJJ96972; ASPACDRAFT_33832.
DR GeneID; 30973807; -.
DR VEuPathDB; FungiDB:ASPACDRAFT_33832; -.
DR OrthoDB; 68112at2759; -.
DR Proteomes; UP000184546; Unassembled WGS sequence.
DR GO; GO:0016746; F:acyltransferase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008152; P:metabolic process; IEA:UniProtKB-KW.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR030918; PT_fungal_PKS.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR Pfam; PF16073; SAT; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..1792
FT /note="Atrochrysone carboxylic acid synthase AacuL"
FT /id="PRO_0000453428"
FT DOMAIN 1717..1791
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 28..272
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 411..846
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 944..1263
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1330..1650
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 581
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1751
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 1792 AA; 194398 MW; C6EF96DD4F637C8B CRC64;
MVTYTPPAEA QDLPTKLKVL YFSNEFPTDD LSTLLRRLHS HSKHSSHPIL ARFLSEATRV
LRNEVSQLRM ELGQLVPAFE SVTTLAGETK LRKGPLAQSI DGVLLCVLQL GMYIGYASHP
LWFFLHCELY PEDQATETNS VLTGLGVGIL VSTAVSVSTS LDDAVTAGVE VLRIAFRLGV
FVANVSHNLE DVDAEASDSW AYVVHGMTVD EAQKELDDIQ AKERTPSASK IFVSAISETS
VTVSGPPSRL KALFRNYASF RDRKFAHLPV YGGLCHAAHI YAREDAQAVV RAPSLPARYK
PVVPVMSTSS GQPFLASSAA ELFEQVIFEV LTKQIVWDNV IRGVAERVAK TDVHDVNIKV
FRHSLPAQQL STALTSAMTD LPVDADDLLA WVGTDVDHGQ YSPGSSMQSK IAIVGMSCRM
PGGATDTEKF WDLLEAGLDV HRRIPADRFD VDSHHDPTGK RMNTSHTAYG CFIDEPGLFD
APFFNMSPRE AEQTDPMQRL AIVTAYEALE RAGYVANRTP ATNLNRIGTW YGQASDDYRE
VNTGQEISTY FIPGGCRAFG PGRINYFFKF AGPSFNCDTA CSSSLATIQA ACTALWAGDV
DTVVAGGLNV LTNSDAFAGL CNGHFLTKTP NACKTWDCTA DGYCRADGVG SIVMKRLDDA
LADNDNILGV IPAAATNHSA NAVSITHPHA GHQSDLYRQV MARAGIDPLD VSYVEFHGTG
TQAGDAEEME SITNVFAPIK GKRRTSKQPL HIGAVKANVG HGEAAAGVTA LIKVLLMLQK
GAIPPHVGIK TSINPGFPKD MERRNLHIPF ETTAWSRTSE KKRIAVVNNF SAAGGNTTLV
LEEGPVRDRL GSDPRPSHVF TVSAKSKISL KGNLQRLIAY LEKNEDVSMA DLAYSLTARR
YHHNHRVAAT ATDTSSLKQQ LISKLDGVDS MKPMPTTGAP PVAFVFTGQG AADKSMNLQL
YHHSPFFRSQ LESLDRLGQQ HGFPSFLPAV DGSYPKDHAW PPVITQVAHT SVEIALARYW
ETLGIKPEVV AGHSLGEYAA FVIAGVLSAS DAIFLVGSRA QMLESLCTAG THKMMAVKAS
RCEIEDAIKD LPYDLACVNG PKETVLSGTT EQMEAVSVPL KEKGYRVIFL DVPFAFHSAQ
TDPILDLFEE TARKSVIFRP PTLPIVSPLL GRVVFDEKSL NAEYLRRATR GTVDFLSAMQ
NAQETSIVDK DTVWVEVGPH PVCVAFIKAS FDPAPVTVGS FRRGEDNWTT LAAGLGQLHT
AGLPVRWGEF HRPFEASLRL LDLPTYSWNE KNYWIQYRGD WALTKGNTFY DAEKGINRQA
AAAPVSSLST TTVQQIIEEN FSGSSGKVVM QSDLMQPDLL AAAHGHKMNN CGVVTSSIHG
DIVYTLGEYL YKKLIPMAKT VHANITDLKV TKGLVAQSNT KVPQYFRVTA TTADIHAGAA
DFVWENVAND GTVSEPFATC RVVYGDADHW LSSWSPLAHL VQGRIETLER LAAEGIANRF
SHKMAYTLFG NNLVEYADKY RGMQAVVMHE FEAFADVTLK HVSGGGSYTV PPYFIDSVAH
LAGFIMNVSD ASDTANTFCV TPGWDSMRFA RPLVPGQRYR SYVKMIPTDD DPSVYLGDVY
VFQDKVIMGM VGGIQFRRYP RILMNRFFAA PDSSIAKSYA AAGGAGPAVS APAPAPPVSP
PKPAVVEAAL QANPSASTPA STPAPAAVTA APAVNSDSTS GKALVLIANE AGLEQSDLTD
DAAFANLGVD SLMSLVIAEK FREELGIVVA GSLFLEYPTI GALRSWLEEY YS
