5MOAS_ASPTN
ID 5MOAS_ASPTN Reviewed; 2590 AA.
AC Q0CRQ5;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 96.
DE RecName: Full=5-methylorsellinic acid synthase {ECO:0000303|PubMed:24412543};
DE EC=2.3.1.- {ECO:0000269|PubMed:24412543, ECO:0000269|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster A protein ATEG_03629 {ECO:0000303|PubMed:31908094};
DE AltName: Full=Non-reducing polyketide synthase ATEG_03629 {ECO:0000303|PubMed:24412543};
DE Short=NR-PKS ATEG_03629 {ECO:0000303|PubMed:24412543};
GN ORFNames=ATEG_03629;
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=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 [3]
RP FUNCTION, CATALYTIC ACTIVITY, DOMAIN, MUTAGENESIS OF SER-1651 AND SER-1772,
RP AND PATHWAY.
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 [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: Non-reducing polyketide synthase; 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 -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + H(+) + 3 malonyl-CoA + S-adenosyl-L-methionine =
CC 5-methylorsellinate + 3 CO2 + 4 CoA + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:63056, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57288, ChEBI:CHEBI:57384,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:146172;
CC Evidence={ECO:0000269|PubMed:24412543, ECO:0000269|PubMed:31908094};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63057;
CC Evidence={ECO:0000269|PubMed:24412543, ECO:0000269|PubMed:31908094};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:24412543, 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 -!- 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 2 acyl-carrier proteins (ACPs) that
CC serve as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm. {ECO:0000305|PubMed:31908094}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of 5-methyl orsellinic
CC acid and azasperpyranone A (AZA-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}.
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DR EMBL; CH476598; EAU35431.1; -; Genomic_DNA.
DR RefSeq; XP_001212807.1; XM_001212807.1.
DR AlphaFoldDB; Q0CRQ5; -.
DR SMR; Q0CRQ5; -.
DR STRING; 33178.CADATEAP00008209; -.
DR EnsemblFungi; EAU35431; EAU35431; ATEG_03629.
DR GeneID; 4318785; -.
DR VEuPathDB; FungiDB:ATEG_03629; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_6_3_1; -.
DR OMA; GACTWLE; -.
DR OrthoDB; 93381at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008236; F:serine-type peptidase activity; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:InterPro.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR013094; AB_hydrolase_3.
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; IPR041068; HTH_51.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR001375; Peptidase_S9.
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; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF07859; Abhydrolase_3; 1.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF18558; HTH_51; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00326; Peptidase_S9; 1.
DR Pfam; PF00550; PP-binding; 2.
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; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 2.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat;
KW Transferase.
FT CHAIN 1..2590
FT /note="5-methylorsellinic acid synthase"
FT /id="PRO_0000449881"
FT DOMAIN 1617..1691
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:24412543"
FT DOMAIN 1736..1812
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:24412543"
FT REGION 6..255
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT REGION 369..731
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT REGION 891..1191
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT REGION 1267..1568
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT REGION 1587..1612
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1980..2212
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT REGION 2282..2590
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24412543"
FT ACT_SITE 534
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 978
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1651
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1772
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 1651
FT /note="S->A: Abolishes the production of both 2,4-dihydroxy
FT 5,6-dimethyl benzaldehyde and 5-methylorsellinic acid; when
FT associated with A-1772."
FT /evidence="ECO:0000269|PubMed:24412543"
FT MUTAGEN 1772
FT /note="S->A: Abolishes the production of both 2,4-dihydroxy
FT 5,6-dimethyl benzaldehyde and 5-methylorsellinic acid; when
FT associated with A-1651."
FT /evidence="ECO:0000269|PubMed:24412543"
SQ SEQUENCE 2590 AA; 283675 MW; A1B168D6712D3FE3 CRC64;
MTPTLLLCGS QAIQWSEDYL SSLREMLLAD SALQPLVHAI RDLPQLWATL LEADTALHKM
PGKQTLDRFT RWLDGERLLE KDSPSDLNMI MSPLTVIMQL VEYISHLHQS NLTHLQILDG
AKHGGIQGFC TGFLAAITLS ISRDESDVAE LGTVALRLAT CIGAYVDLDQ CNSSGFACLA
VRWPTAADER KVKDILETYN GAYLSVRSDV ASATLTVPRA AKSSIIDELS NIGAHVKDIP
LSGRFHNQVN RELFAKLAAL CKSTIGLQFP GHCRPLVPLR SNADGELLSG NEALHVAALN
SLLLHVSDWH KTVSKAMDSL SQTTAEPEVS VLGLGDCIPR TIRQSRALHV SHIKTGSTQS
HDDPYQYPGD SIAIVGMGCR FPGADSLEEY WKVIESATSM LGDLPEGRFP KTNLRRDPNG
KIPLNGNFLR HPDLWDHRFF KRSSREAASM DPQHRLALEV AYEALESAGY FAQRSPAKDI
GCYMGVAASD YEDNVASHAP TAFSVLGMVR AFTSGKISHF FGLSGPSLVF DTACSSSLVA
IHTACRALQA NECSMALAGG VNVITSPTLH QNLGAANFLS PTGGSKSFDD RADGYCRGEG
AGIVLLKRLD RAIAEKDRIL GVIAGSAVNQ NDNAYPVTVP VSMSQTALYR RVLDMSGLSP
RPVSYVEAHG TGTPKGDPIE CASIREVFGG QVNRKLYFGS VKANIGHAEA ASGVAGLIKV
LLMMQKRSIP PQALFASLNK SIPPLEPDNM AIAQRVTPWS EEFYAACVNN YGAAGSNAAL
IVTQPPNIRR GSHAGVALKN CPILLSANTA GSLRQTTVVL REFLAHNRAI SENDLLKSTA
FHLAKRFNPS FKYRHSFSVA SLNQLDEKLQ ICSQLPDSEF LLPPNHRPVV LAFGGQTGNV
VHLSEGVYRG SSILRKYLDK CDMQLRQLGL TSIFPTIFEQ KSIEDTIQLH CTMFSLQYAS
AMAWIAAGLQ VQTVIGHSFG QLTAMCVAGV LSLVDAIRLI AGRATIIQEK WGAERGCMLL
VQGELALVQK LISQAREATS HVVEIACFNG PNSFVLVGSE ADIDAFDGLA ASSLKTRKMA
VTHGFHSRFV DTIMDDYQKL ADSLEYKSPT IAIETCSSGE TWDMFTADKV AKQSRQPVYF
AEAVERIAQR LGSCTWIEAG SGSGITSMAR RALNDTTNHD FHAVNLGGPE PWAAFADTTV
SLWQAGVQVD YWPFHKEQQL EYLPLNLPPY QFERSRHWLA YVDRPGADGL IQSKETQSVE
TKPKLVSFVK YLDSNRQTAE FSIGQDCEQY QALVRGHAVL ANTLCPAALY VEMAAYAASL
LVPDFSPSTY TSRVEDLHMQ SPLAIDLKRG LRLVLSSSGS GTWQFIMQSF SLSDSDNATQ
HASGTVNISS LTSEKLQSRF SRYKRIVNYE RCESLLSDSG TSAIQGSLVY KMFDKVVVYS
DIFRGVSKIA SRGHEVTGQV SLPSAGLELV KDSVCNPLVV DNFTQVAGLH VNSLDDCGSN
EVYLCNGIEQ IDACKPLDAS GSWLVHSSFD RVGTRELVND IFVFDASTKE LVMTLFGLRF
AKVPTASLKR ALERANTVQN PVQTPSLKVT EPSANVPKAQ PVSTYPKPMK PAPAADAQIR
TATMALLNEV ADVPLSDIAD GAQLEDLGID SLMAAELLSA IRERFNLDIP TSTFASIVDF
KGLYQHIASG TDAGILTPSS SGMESDDSIL EVQYTDTSTP FSEIAYPLED KDAGDSAQAG
QIAQLSQLFA EHLECPLPIP SGETLRDIGL DSLVGMELAA DIQQAFGRKV DLATLDPECT
FGQFCDMVIP KPTLSVPTVS EKVDKTVRWA STEIAYTAKR ENKMQDPVEM QSDGGNVNYL
AHCAEDFAQI RKNYTTFAKQ TGFADFRANV YPQQKELVCA YVTEAFAALG SDLKTIPSGS
PLPPIQHIAR HAKVMKQYYK VLEDSGLITI TDNGPIRTAK PVSPVKSEDL YQMIYSAFPQ
HRGEHKLLNS TGSKLASCLK GETDPLQILF GSKASKDLME DVYTNSPMFA TGTRILGDFF
VKTFSKYKGP EKLRILELGA GTGGTTKYIV EKLLEHNIPF TYTFTDLSPS LVALAKRKFS
HYGCLEFLVL DIEKTPPEHL TNSYHAILSS NCVHATKNLL NSTTNTRKLL RADGFLCLLE
LTRNLFWLDC VFGLLEGWWL FEDGRKHVLA DEYLWKETLL EAGFRHVDWS DDDTEESDQF
RVITGFVADI GHNALDQAKP VTTKLPTMET TSFATVDGIP LLADIYYPTK PDAPGVKRPI
ALMIHGGGHI MLSRRDIRPK QTRLLLERGL LPVSIEYRLC PEVSLTEGPI PDACAALNWV
RTVLPTLRLQ RPDIHPNGDK VAVVGWSTGG TLSMMLAFSA PQRGIRPPDA ILAFYCPTDY
EAEFFRTPNY PEDTSEVVPE IYDILEGVQE RPITAYNVPA HQGATGGWMS LSDPRSRIAL
HMNWRGQMMP VLLDGLPSKK TLLEAGGDAS PSKWMDLPQP SVDRLRAVSP YAQIVQGNYR
VPTFLVHGTR DDLIPWEQSV RTKDALTSQG VAAGVAVVDD AVHLFDLYRD PEGRYWNAVL
EGYEFLLRHL
