AZAB_ASPNA
ID AZAB_ASPNA Reviewed; 2533 AA.
AC G3XMD1;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 14-DEC-2011, sequence version 1.
DT 03-AUG-2022, entry version 55.
DE RecName: Full=Highly reducing polyketide synthase azaB {ECO:0000303|PubMed:22921072};
DE Short=HR-PKS azaB {ECO:0000303|PubMed:22921072};
DE EC=2.3.1.- {ECO:0000269|PubMed:22921072};
DE AltName: Full=Azaphilone biosynthesis cluster protein azaB {ECO:0000303|PubMed:22921072};
GN Name=azaB {ECO:0000303|PubMed:22921072}; ORFNames=ASPNIDRAFT_188817;
OS Aspergillus niger (strain ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 /
OS NCTC 3858a / NRRL 328 / USDA 3528.7).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=380704;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 1015 / CBS 113.46 / FGSC A1144 / LSHB Ac4 / NCTC 3858a / NRRL
RC 328 / USDA 3528.7;
RX PubMed=21543515; DOI=10.1101/gr.112169.110;
RA Andersen M.R., Salazar M.P., Schaap P.J., van de Vondervoort P.J.I.,
RA Culley D., Thykaer J., Frisvad J.C., Nielsen K.F., Albang R., Albermann K.,
RA Berka R.M., Braus G.H., Braus-Stromeyer S.A., Corrochano L.M., Dai Z.,
RA van Dijck P.W.M., Hofmann G., Lasure L.L., Magnuson J.K., Menke H.,
RA Meijer M., Meijer S.L., Nielsen J.B., Nielsen M.L., van Ooyen A.J.J.,
RA Pel H.J., Poulsen L., Samson R.A., Stam H., Tsang A., van den Brink J.M.,
RA Atkins A., Aerts A., Shapiro H., Pangilinan J., Salamov A., Lou Y.,
RA Lindquist E., Lucas S., Grimwood J., Grigoriev I.V., Kubicek C.P.,
RA Martinez D., van Peij N.N.M.E., Roubos J.A., Nielsen J., Baker S.E.;
RT "Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015
RT versus enzyme-producing CBS 513.88.";
RL Genome Res. 21:885-897(2011).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, DOMAIN, AND INDUCTION.
RX PubMed=22921072; DOI=10.1016/j.chembiol.2012.07.004;
RA Zabala A.O., Xu W., Chooi Y.H., Tang Y.;
RT "Characterization of a silent azaphilone gene cluster from Aspergillus
RT niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation.";
RL Chem. Biol. 19:1049-1059(2012).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of azaphilones, a class of fungal
CC metabolites characterized by a highly oxygenated pyrano-quinone
CC bicyclic core and exhibiting a broad range of bioactivities
CC (PubMed:22921072). In the first step, the non-reducing polyketide
CC synthase azaA forms the hexaketide precursor from successive
CC condensations of five malonyl-CoA units, presumably with a simple
CC acetyl-CoA starter unit (PubMed:22921072). The reactive polyketide
CC chain then undergoes a PT-mediated C2-C7 cyclization to afford the
CC aromatic ring and is eventually released as an aldehyde through the R-
CC domain (PubMed:22921072). The putative ketoreductase azaE is proposed
CC to catalyze the reduction of the terminal ketone resulting in the early
CC culture product FK17-P2a (PubMed:22921072). The monooxygenase azaH was
CC demonstrated to be the only enzyme required to convert FK17-P2a to
CC azanigerone E (PubMed:22921072). AzaH first hydroxylates the
CC benzaldehyde intermediate FK17-P2a at C4, which triggers the formation
CC of the pyran-ring to afford azanigerone E (PubMed:22921072). In
CC parallel, the 2,4-dimethylhexanoyl chain is synthesized by the HR-PKS
CC azaB and is proposed to be transferred to the C4-hydroxyl of
CC azanigerone E by the acyltransferase azaD directly from the ACP domain
CC of azaB (PubMed:22921072). Alternatively, the 2,4-dimethyl-hexanoyl
CC chain may be offloaded from the HR-PKS as a carboxylic acid and
CC converted to an acyl-CoA by azaF (PubMed:22921072). The resulting acyl-
CC CoA molecule could then be taken up as a substrate by AzaD to form
CC azanigerone B (PubMed:22921072). To yield the carboxylic acid
CC substituent in azanigerone A, the hydroxypropyl side chain of
CC azanigerone B would need to undergo a C-C oxidative cleavage catalyzed
CC by cytochrome P450 AzaI (PubMed:22921072). AzaI is proposed to act on a
CC vicinal diol that leads to a C-C bond scission either through an
CC alkoxyradical intermediate or a peroxy complex (PubMed:22921072). In
CC the biosynthesis of azanigerone A, azanigerone B first undergoes
CC hydroxylation at C10, possibly catalyzed by one of the two FAD-
CC dependent monooxygenases encoded in the cluster, azaG or azaL,
CC resulting in the vicinal diol azanigerone C (PubMed:22921072).
CC Oxidative cleavage of azanigerone C by azaI would yield the
CC corresponding aldehyde derivative of azanigerone A (PubMed:22921072).
CC Finally, the dehydrogenase azaJ is proposed to convert the aldehyde
CC functional group into the carboxylic acid, completing the conversion
CC from azanigerone B to azanigerone A (PubMed:22921072). Alternatively,
CC the oxidation of aldehyde to carboxylic acid may be catalyzed by the
CC same P450 enzyme azaI via consecutive oxidation or by endogenous
CC alcohol dehydrogenase (PubMed:22921072). {ECO:0000269|PubMed:22921072}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:22921072}.
CC -!- INDUCTION: Expression is under the control of the azaphilone cluster-
CC specific transcription factor azaR (PubMed:22921072).
CC {ECO:0000269|PubMed:22921072}.
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:22921072}.
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DR EMBL; ACJE01000001; EHA28244.1; -; Genomic_DNA.
DR AlphaFoldDB; G3XMD1; -.
DR SMR; G3XMD1; -.
DR EnsemblFungi; EHA28244; EHA28244; ASPNIDRAFT_188817.
DR VEuPathDB; FungiDB:ASPNIDRAFT2_1148627; -.
DR HOGENOM; CLU_000022_31_0_1; -.
DR Proteomes; UP000009038; 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:0016491; F:oxidoreductase 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; -; 1.
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; IPR013149; ADH-like_C.
DR InterPro; IPR011032; GroES-like_sf.
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; 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; PF00107; ADH_zinc_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
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; 2.
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 Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW Transferase.
FT CHAIN 1..2533
FT /note="Highly reducing polyketide synthase azaB"
FT /id="PRO_0000437589"
FT DOMAIN 2455..2532
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:22921072"
FT REGION 10..436
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT REGION 554..821
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT REGION 947..1251
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT REGION 1419..1554
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT REGION 1839..2155
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT REGION 2178..2349
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22921072"
FT ACT_SITE 180
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2492
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2533 AA; 277485 MW; 5A7582DE063E39E9 CRC64;
MAGEYSTAPM AIIGMACRFS GGATSPEKLW DMIVQRRSGW SEIPTSRFNA NGLYHPNGER
VGTTHVKGGH FLEDDIACFD AAFFGMASET ASAMDPQYRM ELEVVYEALE SAGIPMESIK
GTNTSVYGGV MFRDYHDTHS RDLDTLPRYF MTGNAATMAS NRISHFYDLR GPSMTVDTGC
STSLTALHLA CQNLRSGESN MSIVTGASLM INPDVFLSMS NIGFLSPDGI SYAFDSRANG
YGRGEGVGAL LVKRLDDALR DGDSIRAIIR ETGVNQNGKT PSITAPQQAA QEALIRQCYE
RVNLDPAQTT YVEAHGTGTP AGDPLEVGAL AAALGGSRSA EHPLYLGSIK ANIGHTEAAS
GVASIIKVAL ALEKGQIPPN TQLNTPNSEL RLNDRNMEVP VSTQRWPVGK GPRRASVNNF
GFGGSNAHAI LESPPVENGA NRTNGQLKSN GPVVNGNKTN ITKRETPWVF RLSAKDAQTC
QQMAADLSTY IESHPPVDEE AFLGRLAYTL GSRRSVFSWT AAVSARSLAE LTRALDDDER
LVPSRAAPSL RLGWVFTGQG AQWYAMGREL IATYPVFRST ILECDRYMTE MGSTWTLMEE
LHREESTSQV NNIVYSLGLA TAIQIALVEL LWSWGIHPTA VTGHSSGEIA AAYASKALDM
KSAIGIAYLR GVLAEKFDDK ILGKGGMMAV GLGRKPVEHY LSRVTAGYCV VACVNSQYSV
TISGDIPAID QLEQLLQEDQ VFARRLRVNG AFHCEQMRPM ADLFDWSLRY LLTPHPDFGS
VLFSSPKTGS RIQDGTILAT SSHWVGNMLQ AVEFESSFRH MCFGDPSPKG AKGTQDVDLV
LEIGPHGALG GPIQQLMTLP EFEGSGISYL PTLVRKQDAV FAMQRLAIDL THRGYPVDLN
AVNFPHGTLS LSILHDLPSY PWNHSTRYWL EPRRNRADRQ RQAPPSDLVG YSQPSITPLA
RTWRHIIRLS DLPWLGDHRV QSSIVFPGAG LVSMAIEGMR QVAAGRQQTV SAYELRDVDI
AKALTVPEAD EGVEVQLNIR PCDEQMLGTK DWLAFQIFSV SGDSRWTEHC SGRISVITTS
DSTPLPSAIP SQSEDLYNRR IDPRYMWAAM RSVGIYHGPL FQNIHQVLAK PSASRTIFAI
ADTAAVMPKK YQTPHVLHPT TLDSVFQAAY TLLPESGARL PSAMVPRHIR SVRVSAQISN
SPAHELEAYA TLNRDYDAQS FETSLTVVDA KDGNSPVLEV DGLTCQSLGR ALDREADPHE
NEICSRWEWA PDIGTLDAAA CKDRIRCAPE AAEIETMRDL RRATILYILD IVSSLTVADV
QQLRGHLKKF YVWMVEQLKK ASRNQFAPDS AQWRDISAAD KAALYEKVGR TSVNGEMLCR
LGPLGASFLR QEMAPLEVML ENRLLFRYYL EALKWDRSTR QVSELVRLCT HKNPRAKILE
IGAGTGGGTQ VILEALGKEN GSSTGARFGR YDFTDISAGF FEAAKERFQD WADLMNFQKL
DIEHDPVAQG FEEGSYDVVI ACQVLHATKS MDRTLTHVRK LLKPGGKLIL METTRDELDV
FFAFGLLPGW WLSEEEERRT TPSLTLPFWN QVLSRNGFAG LDLEVHDCDS EEFYAFSTIL
STAQAPALSI TSPVTIVTGT SPPPTSWMSE LQTAVAAHIG CQPVIATLET VTPQGNICIF
LGEADEPLLD HVSNPVEFDR IIHLATRCKG LLWITRGGSL DVDKPAMSLS QGLLRTLKSE
YQGKSFVSLD VDPRRSPWTA EVVQAISQIF PASFSETTDP ATCEFEYAER DGVLHIPRTV
KDIPMNRNIF PESDTTEKTI HCRFRDAARP LRMKIGTPGL IDTLVFHDDL DAKSDPLPAD
WIEFDPTAFG LNFRDVMVAM GQLEANAIMG FECAGTIVRL GATAAAKGFA VGDRVCTLLR
GHWATRPRAP WTSVMRIPQH LSDQEAASFP TVFATAYIAL HETARLQRGE SILIHAATGG
VGQAAIQLAQ LIGAEIYATA STPAKRQLLH ETYGIPENNI FSSRDPSFAT DVHLRTDGRG
VDVVLNSLAG RLLQESFNCL AEFGRMVEIG KRDLEQHSGL DMYPFTRNVS FSSVDLLTWQ
SRRGADISCV LQSLSKLLGE KKIMPVYPLT LYPITQIEKA FRTMQTGQHM GKIIISVGEQ
DTVPVVERPP PFSLRSDASY VIVGGLGGIG RVLCEWMMAR GARHLIIISR NARPGPFVTE
LEQQGCEVRT LACDIAAEDQ LAAALAQCAD MPPIKGVIQG AMVLKDTVLE QMTVGDFEAA
VRPKAQGSWN LHQQLGDVDF FIMLSSLMGV MGAASQANYA AGGAFQDALA TYRRNRGLPA
VSLDLGIVRS VGFVAQTDGV QERLVQMGVT SLSEETVLRI LEQAITHPTG PPQIITGINT
APGKHWDEAS WIQDPRFAAL RYRDSTQAGS SRATTGTAKQ GKIRDQLAEI ASPVDAAALI
CQELMQKLAS MFGLVVEEMS ATQDLSSYGV DSLVAVELRN WLVAQVGAEV SIFDLMQSPS
LEDLSLRVAT KRT
