AZPB2_ASPTN
ID AZPB2_ASPTN Reviewed; 2737 AA.
AC Q0CF73;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=Non-reducing polyketide synthase ATEG_07661 {ECO:0000303|PubMed:31908094};
DE Short=NR-PKS {ECO:0000303|PubMed:31908094};
DE EC=2.3.1.- {ECO:0000305|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster B protein ATEG_07661 {ECO:0000303|PubMed:31908094};
GN ORFNames=ATEG_07661;
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, CATALYTIC ACTIVITY, AND PATHWAY.
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.
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, 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: Non-reducing polyketide synthase; 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 -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|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 -!- DOMAIN: Multidomain protein; including an N-terminal starter unit:ACP
CC transacylase (SAT) domain, a beta-ketoacyl synthase (KS) domain, a
CC malonyl-CoA:ACP transacylase (MAT) domain, a product template domain, a
CC acyl carrier protein (ACP) domain, a methyltransferase domain and a
CC reductive NADPH-binding domain that is required for NADPH-dependent
CC product release. {ECO:0000305|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; a methyltransferase domain; a reductive
CC NADPH-binding domain that is required for NADPH-dependent product
CC release; and an acyl-carrier protein (ACP) that serves as the tether of
CC the growing and completed polyketide via its phosphopantetheinyl arm.
CC {ECO:0000305|PubMed:31908094}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of azasperpyranone
CC 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; CH476604; EAU31923.1; -; Genomic_DNA.
DR RefSeq; XP_001216282.1; XM_001216282.1.
DR SMR; Q0CF73; -.
DR STRING; 33178.CADATEAP00001525; -.
DR EnsemblFungi; EAU31923; EAU31923; ATEG_07661.
DR GeneID; 4323014; -.
DR VEuPathDB; FungiDB:ATEG_07661; -.
DR eggNOG; KOG1178; Eukaryota.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_6_2_1; -.
DR OMA; WHVYARH; -.
DR OrthoDB; 13314at2759; -.
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:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
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 Gene3D; 3.40.50.150; -; 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; IPR013120; Far_NAD-bd.
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; IPR036291; NAD(P)-bd_dom_sf.
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; 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; PF07993; NAD_binding_4; 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; SSF51735; SSF51735; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2737
FT /note="Non-reducing polyketide synthase ATEG_07661"
FT /id="PRO_0000450085"
FT DOMAIN 1750..1824
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 75..245
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 430..857
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 969..1260
FT /note="Malonyl-CoA:ACP transacylase (MAT)"
FT /evidence="ECO:0000255"
FT REGION 1399..1681
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1724..1747
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1827..1876
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2094..2270
FT /note="Methyltransferase domain"
FT /evidence="ECO:0000255"
FT REGION 2362..2665
FT /note="NADPH-binding domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 1849..1868
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 154
FT /note="Nucleophile; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 276
FT /note="Proton donor/acceptor; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 603
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 1784
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2737 AA; 299142 MW; DFE1562184AB5723 CRC64;
MTHTTGPTKA SGESTIFLFG PHVGTFTKQS MNKLVHPLSQ SPQRDWILDT IAELPGYWDA
LAAKMPDVAR DIDGSRSLAE LDSWLRHGSA NLGEDDSNLP SIIVGPLVVF IQLTQYWRHL
ELTKAGTQAT DLQADLVAMH SNQTGDKVEI LGFCAGLLAA LAVASSNNRQ EFQKYGAVAV
RLAMLIGALI DAQEVWDKAS GKGSSSSYAV AWRGPKQEED MTRIIDDLAA NAYIAVRYDQ
TRATVTASET IAPLLLKRFR AAGITVAEVG IKGQIHSPNP DRRAHTNALV DLCNSLPGLQ
YAAAERLALQ TYDNQGDGKP LLPDRGSLTE MVLRSILVQQ CHWYDTFSAV TERHQDPYVV
TFGLERCVPP TLMRSLGGRQ VFFEDLPKDP SHPSSWMPNA PHGPQQQLQQ RQLPVEVHTK
PAFDVSNEAI AIVGMSVKTA GADDLAEFAE MLKTGQSQHI PITRDRLMHD MLFRESADSD
PKRKYYGCFF RDGDAFDHKF FKRSPREAAA MDPQSRIVLQ TAYQAIEQSG YFAEDHTGYT
PDGRDKAHVG VYLGSCGVDY EHNISCHDPN AFTATGALKS FITGRVSHLF GWTGPCMTFD
TACSSSAVAI HTACRNLLSG ECTAALAGGS NTVTNMNWFQ NLAAGSFVSP TGQCKPFDDD
ADGYCRAEGA AFVFLKRLSD AVRDGNPILA TIASSAVYQN QNCTPLFVPN SPSLSHLFKD
VMHQAKITAN DVSLVEAHGT GTPVGDPAEY ESIRVALGGP IRKKTLPIGS VKGHIGHTEG
ASGAIALVKI IMMMREGFIP PQASFKKMNR KIPVRADDNM EVVTKLRPWD EPHKTALLNN
YGACGSNASM IITEPDKALS GPIDGSRYRN TGQRYPFWIP GFDSRAITAY CAKLGSWLRS
CRQEPTLADV SFNVNRQSNR SLTQGFIFNC RSMTELHEKL EQAAAAGKDA AANAGITPVK
AERPVVLCFG GQVSRFVGLD RNLFESVAIL RQHLDHVDAV VTSQGLGSIY PEIFEREPVR
DTVKLQTMLF ALQYACAKSW MDSGLQGKVQ AVVGHSFGEI TALCIAGVLS LEHTVQLVAA
RAALVRDNWG ADPGAMMAIE ADENLVNELL LEANRGSDGS ASIACYNGPR SFTIAGSTGA
IDAVQQTMGS NSKFGSIKSK RLSVTNAFHS ALVDKISDGL ERIGKTLTFH RPIIPVERAT
EMPFDMDNLD GSFVSQHMRQ PVYFNHALQR LVKRYPQAIF LEAGSSSTIT IMASRAIAQS
QASSSDAHHF QAMSITSDTA FDSLTDATMA LWKQGLRVSF WAHHAVQARD YAQLLLPPYQ
FDTSSRHWLP MKSPLEEVKK AAAAMVAAGG DVGTGQHQQN DALQDPRLQS LWNFVEFQDG
DNKKPRFRIN TGSDKYNRFV LSHVIAQTAP ICPGTLECDI VIEALFSLEP TWKQEGVQPV
VRDMINHSPI CKDPSRTVYL DLTALNKKRT QWTVRIFSVD SNSSRQASET HAEASVEMRA
PTDAAHLREF ANFERLVSHQ QCLDVLRLNL DEEGVEVLQG RNVYRAFNPI VDYGDVYRGV
RYVVGRGNEC AGSVQLPKCH RGDTWLDVPL SDSFSQVGGI WVNLLTDLPP SDMYIATGCG
LSMRSPTAPP RADTDVWHVY ARHSRQGDKA FMTDLFVFDP ATGQLVELML GVQYGRVAKA
SMSMMLARMT KDESVLRTKT PSSSHPAPTV KSVPIEASVA VKASRTTKKK AKASKSKSSV
KKDKAPSGWR DITDEVRNLV ATVSGIEASE LELDSEMADF GIDSLMGMEL GKEVETAFKC
TLDQNEQMEA TTLRKFVACV SNALFGPNQG QSSIDEDDED DEHSEDSSNE SSSAASDEDA
SSGLESPDTG ILTPEDEPLP LKAVAIHKAA GLAAIAPPVE SHLALSASDI LESFGEVKMT
TDRLMHEYGV HKTEKVMLAG SNRLCAALVV EAFDELGSPL RTAAAGQVID RVPFLPQHGR
LMQWVYEFLE RDARLIDIDV TSGQITRTHI APPRKTSHAI LQELLASDPD FAVPNRLAYY
AGKQLAGVLS GSTDGIRVLF GSPEGRELTA AMYCEHTFNC MSYAQMREVT KILADRIQSS
SGSSGETFKV LEMGAGTGGT TLVMAPLLAS LSDMGMAVEY TFTDISPSMV ANARRRFSKL
YPFMRFSVHD IEKAPADELK GQHLVLASNA IHATHNLGVS LSNIHQALRP DGFLMMLEMT
EVVPFVDLVF GLLEGWWLFD DGRSHAVVPA EHWERELHAA GFGHVDWTDG SLPENAFQKV
IIALASGTQG PRLPKPASVP EPIPELNPKS IETRTAHAEQ LTATYSKGWA TPKLRALDAK
SEEGQVKPSG TSRLRKVDLG AVVLVTGATG SLGSHLVQKL ADDPNVAQVV CLNRRSNSMP
ADKRQQEALA TRGITLSPGG RAKLRILETD TSKAQLGLPP LEYSWLVEHG TDIVHNAWPM
SGTRPVSAFE PQLQAMRNLL DLARDMACRD INPPSRVGFQ FVSSIGVVGF VGESRVTERR
VPLSATLPSG YGEAKWVCER MLDETLHKYP RLFRPMVVRP GQISGSSTSG FWNPVEHFAF
LVKSAQALRA WPDLDGVLQW IPVNFCAGII VDLLKIASRA DDAYPVYHID NPVGQPWKAM
NPVLASALDI PPHAIIPFKD WISRVRRSPL PLETENPAAR LVDFLDDHFE RMSCGGLVLD
TSKALEHSQT MATVGPVSSD VARLYVASWK KMGYLHS
