AZPB1_ASPTN
ID AZPB1_ASPTN Reviewed; 2611 AA.
AC Q0CF75;
DT 17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 111.
DE RecName: Full=Highly reducing polyketide synthase ATEG_07659 {ECO:0000303|PubMed:31908094};
DE Short=HR-PKS {ECO:0000303|PubMed:31908094};
DE EC=2.3.1.- {ECO:0000305|PubMed:31908094};
DE AltName: Full=Azasperpyranone A biosynthesis cluster B protein ATEG_07659 {ECO:0000303|PubMed:31908094};
GN ORFNames=ATEG_07659;
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: Highly reducing polyketide synthase; part of the cluster B
CC that 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 a ketosynthase (KS) that
CC catalyzes repeated decarboxylative condensation to elongate the
CC polyketide backbone; a malonyl-CoA:ACP transacylase (MAT) that selects
CC and transfers the extender unit malonyl-CoA; a dehydratase (DH) domain
CC that reduces hydroxyl groups to enoyl groups; a methyltransferase
CC (CMeT) domain responsible for the incorporation of methyl groups; an
CC enoylreductase (ER) domain that reduces enoyl groups to alkyl group; a
CC ketoreductase (KR) domain that catalyzes beta-ketoreduction steps; and
CC an acyl-carrier protein (ACP) that serves as the tether of the growing
CC 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}.
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; CH476604; EAU31921.1; -; Genomic_DNA.
DR RefSeq; XP_001216280.1; XM_001216280.1.
DR AlphaFoldDB; Q0CF75; -.
DR SMR; Q0CF75; -.
DR STRING; 341663.Q0CF75; -.
DR EnsemblFungi; EAU31921; EAU31921; ATEG_07659.
DR GeneID; 4323012; -.
DR VEuPathDB; FungiDB:ATEG_07659; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_5_1; -.
DR OMA; GPGPHWD; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; 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; IPR011032; GroES-like_sf.
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; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
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; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 2.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW Transferase.
FT CHAIN 1..2611
FT /note="Highly reducing polyketide synthase ATEG_07659"
FT /id="PRO_0000450084"
FT DOMAIN 2527..2604
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 13..410
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 537..844
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 970..1289
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1469..1602
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1898..2213
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2236..2416
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT REGION 2499..2520
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 157
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2564
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2611 AA; 282647 MW; 4A2D38FD22848283 CRC64;
MGSTHNEWES EPIAIIGLSC KFAGDASNPE KLWDMLAEGR NAWSEVPSSR FNPKAVYHPD
SEKLSTTHVK GAHFIDEDIG LFDAAFFNFS AETAAIAGSN TSVYAGVFTH DYHEGLIRDE
DRLPRFLPIG TLSAMSSNRI SHFFDLKGAS MTVDTGCSTA LVALHQAVLG LRTGEADMSI
VSGCNLMLSP DMFKVFSSLG MLSPDGKSYA FDSRANGYGR GEGVASIVIK RLKDAVEAGD
PVRAVIRESF LNQDGKTETI TSPSQAAQEA LIRECYRRAG LSPHDTQYFE AHGTGTPTGD
PIEARSIAAV FGQDRSEPLR IGSVKTNIGH TEAASGLAGL IKVVLAMEKG QIPPSVNFQK
PNPKLQLDEW RLKVATELEP WPAASDQPWR ASVNNFGYGG TNSHVIVEGV GSLASLLPRK
QLTNGIHHAV DSKADVKTQS KVLVFSGRDE QACQRMVSNT KEYLERRKLQ DPGMTADKIN
ELMQNLAWTL TQHRSRFAWV SAHAVKYSDN LDQVIQGLDA PQFKPVKVAT TPARIGMVFT
GQGAQWHAMA RELIDPYPVF RSSLYEAERY LRDIGADWSL TAELMRDAAT TRVNDTGLSI
PICVAVQIAL VRLLRSWGIV PSAVTSHSSG EIAAAYTVGA LTLRQAMAVA YYRAAMAADK
TLRGADGGPK GAMVAVGVGK EAAEGYLHKL PSTSGKAVVA CINSPSSITI AGDEAAVQEV
EALATADGVF ARRLKVDTGY HSHHMDPVAE PYRQALRTAL AQKDSDEGQA LPDKVDGEPW
AGAYRAALHE ALPDAIEKGS LDSIIFSSPV TGGRVTRAEV LADPEHWVRS LVQPVRFVEA
FTDMTVGGNG EQERSNVDVI LEVGPHTALG GPIKEILSLP EFEGITLPYM GCLVRKEDAR
DCMLAAAVNL LGKGQPANLT RINFPWGLQG PAKPRVLTDM PSYPWNHSNR HWNESRRNQA
YRQRSQEPHD LLGVLVPGTN PDAASWRHIV RLSEAPWLRD HVVQGNILYP GAGFVCLAIE
AIKMQTAMAS ATPDAGELAG FKLRDVEIHQ ALVIADTADG VEVQTILRPV DGKTIGARGW
KQFEIWSVTA DSEWTEHARG LITVQMAADT AKTNATSHSS ASFLDESGYT RRIDPQDMFA
SLRAKGLNHG PMFQNTVSIL QDGRAKEPRC VVTIKVADTS SPKDKGRDLQ NVLHPTTLDS
IVLSSYAAVP SADPSNDDSA RVPRSIRKLW VSNRISNTPG HVFTCNVKMP HHDAQSYEAN
VSVLDQDGTS EVEPLLEMQG LVCQSLGRSA PGEDKEPWNK ELCANVEWGP DLALSLGLPG
AQDAIDKRLN TLRDEVAGTD SRSIEVQTVL RRVCVYFSHD ALEALTETDV ANLASHHVKF
YKWMKDTVSL AASRRWSAES DTWTSDPPAV RQHYIDLAAK QSVDGELICH LGPLLLPILR
GERAPLEVMM EDRLLYKYYA NAYRLEPAFG QLKSLLAAVL HKNPRARVLE IGAGTGAATR
HALKTLGTDE DGGPRCESWH FTDISSGFFE AARTEFSAWG NLLEFDRLDI EQSPEAQGFK
LASYDVVVAC QVLHATKSMA RTMSNVRSLM KPGATLLLME TTQDQIDLQF IFGLLPGWWL
SEEPERHSSP SLSIGMWDRV LKGAGFTGVE IDLRDVNVDA ESDLYGISNI LSTAASPSPE
LDSSRVVIVT SDKAPPQSGW LETLRKSIAQ VAGNRVLPDV LALESPGLTA ATYTGKLCVF
VGELDKPVLA GLDAADLQGL KTMALGCKGL LWITRGGAVE CTDPESALAS GFVRVLRTEY
LGRRFLTLDL DPRTAEMDTA AIVQVLKSCL AASDAPAPIE SEFAVRDGLI LVPRLYKDVV
WNALLEPEVP DWASPETIPE GPLFQPKRPL RLEVGIPGLL DTLAFGDDDG VAADLPDDMV
EIEPRAYGLN FRDVMVAMGQ LRERVMGLEC AGIITRVGSE AAAQGFAVGD HVMALLLGPF
SSRPRITWHG VINMPQGMSF SDAASIPMIF TTAYVALVQV ARLRHGQSVL IHAAAGGVGQ
AAVMLAQDYL GAEVYATVGS QEKRDLLTRE YGIPPERIFN SRDASFAPAV LAATGGRGVD
AVLNSLGGSL LQASFEVLAP FGNFVEIGKR DLEQNSLLEM ATFTRAVSFT SLDMMTLLRQ
RGPEAHRILS ELARLAGQKI IKPVHPVTVY PMGQVDKAFR LLQTGKHLGK LVLSTEPEEQ
VKVLPRPATP KLRSDASYLL VGGVGGLGRS LANWMVDHGA RNLILLSRSA GKQDTSAFVA
QLREAGSRVA AISCDVSDKE DLAKALRICE HDLHFPPVRG VIQGAMVLQD SILEQMTIDD
WQAAIRPKVA GTWNLHERFS QRGSLDFFVM LSSLSCILGW ASQASYAAGG TYQDALARWR
CASGLPAVSL DMGVIKDVGY VAESRTVSDR LRKVGQSLRL SEESVLQTLA TAVLHPFGRP
QVLLGLNSGP GSHWDPASDS QMGRDARFMP LRYRKPAASR AQAQQAGGDS DSEPLSAKLR
TAESSDAAAR CVGDAIATKL ADIFMVPVDD IDLSKPPSAY GVDSLVAVEL RNMLVLQAAC
DVSIFSILQS ASLAALALDV VAKSAHVEIA A
