BREF7_EUPBR
ID BREF7_EUPBR Reviewed; 2373 AA.
AC A0A068ABB7;
DT 18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2014, sequence version 1.
DT 03-AUG-2022, entry version 36.
DE RecName: Full=Highly reducing polyketide synthase {ECO:0000303|PubMed:24845309};
DE Short=HRPKS {ECO:0000303|PubMed:24845309};
DE EC=2.3.1.- {ECO:0000269|PubMed:24845309};
DE AltName: Full=Brefeldin A biosynthesis cluster protein {ECO:0000303|PubMed:24845309};
GN Name=Bref-PKS {ECO:0000303|PubMed:24845309};
GN Synonyms=orf7 {ECO:0000303|PubMed:24845309};
OS Eupenicillium brefeldianum (Penicillium brefeldianum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=1131482;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTION, FUNCTION, CATALYTIC ACTIVITY,
RP DOMAIN, AND PATHWAY.
RC STRAIN=ATCC 58665;
RX PubMed=24845309; DOI=10.1021/cb500284t;
RA Zabala A.O., Chooi Y.H., Choi M.S., Lin H.C., Tang Y.;
RT "Fungal polyketide synthase product chain-length control by partnering
RT thiohydrolase.";
RL ACS Chem. Biol. 9:1576-1586(2014).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of brefeldin A (BFA), a protein
CC transport inhibitor that shows antiviral, antifungal, and antitumor
CC properties (PubMed:24845309). The proposed biosynthesis of BFA involves
CC formation of an acyclic polyketide chain that is differentially
CC tailored throughout the backbone (PubMed:24845309). The highly reducing
CC polyketide synthase Bref-PKS is proposed to synthesize the precisely
CC reduced octaketide precursor, which could then be directly offloaded by
CC the thiohydrolase enzyme Bref-TH followed by a cytochrome P450
CC monooxygenase-mediated formation of the cyclopentane ring and
CC macrocyclization to afford 7-deoxy BFA. Alternatively, the first ring
CC annulation can also occur on the ACP-tethered intermediate before the
CC thiohydrolase release and lactonization (PubMed:24845309). The C7-
CC hydroxylation by another cytochrome P450 monooxygenase is believed to
CC be the final step in the process to obtain the final structure of BFA
CC (PubMed:24845309). In addition to the HRPKS Bref-PKS and the
CC thiohydrolase Bref-TH, the brefeldin A biosynthesis cluster contains 4
CC cytochrome p450 monooxygenases (called orf3 to orf6), as well a the
CC probable cluster-specific transcription regulator orf8
CC (PubMed:24845309). {ECO:0000269|PubMed:24845309}.
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000250|UniProtKB:Q9Y8A5};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000250|UniProtKB:Q9Y8A5};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:24845309}.
CC -!- INDUCTION: Coexpressed with the other cluster genes on brefeldin A
CC production optimized medium. {ECO:0000269|PubMed:24845309}.
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; an enoylreductase (ER)
CC domain that reduces enoyl groups to alkyl group; a ketoreductase (KR)
CC domain that catalyzes beta-ketoreduction steps; and an acyl-carrier
CC protein (ACP) that serves as the tether of the growing and completed
CC polyketide via its phosphopantetheinyl arm.
CC {ECO:0000305|PubMed:24845309}.
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DR EMBL; KJ728786; AIA58899.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A068ABB7; -.
DR SMR; A0A068ABB7; -.
DR GO; GO:0016746; F:acyltransferase 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:0009058; P:biosynthetic process; IEA:UniProt.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
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; IPR013154; ADH_N.
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; 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; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF08240; ADH_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; 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; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2373
FT /note="Highly reducing polyketide synthase"
FT /id="PRO_0000444935"
FT DOMAIN 2294..2370
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:24845309"
FT REGION 22..449
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24845309"
FT REGION 560..874
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24845309"
FT REGION 942..1241
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24845309"
FT REGION 1669..1985
FT /note="Enoyl reductase (ER) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24845309"
FT REGION 2010..2187
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:24845309"
FT ACT_SITE 192
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 192
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 652
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 974
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2330
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2373 AA; 257334 MW; 0E684BC86CF00D14 CRC64;
MAPHNSLDDT PLSSRTFIQE PIAVVGIACR LPGHSSTPKK LWDFLERGGI AANDTPSTRF
NLAAHHDGSK KPKTMRTPGG MFIEDADPRD FDAGFFGISG ADAAAMDPQQ RQLMEVVYEC
LENSGVPFEK LYGAQVACHV GSYAVDYDAI QARDPEDRAP GAVVGIGRAM LSNRISHFFN
FKGPSMTIDT ACSGSLVGLD VACRYLHTGE VDGAIIGGAN MYFSPEHNLN TGAMSVANSL
SGRCHTFDVK ADGYCKAEAI NCVYLKRLSD AVRDGDPIRA VIRGSATNSD GNTPGIASPN
SAAQAAAIRS AYANAGITNL NDTSYLEFHG TGTQAGDPLE AGGVASVFSA SRKPEAPLYI
GSVKSNIGHS EPAAGISGLI KAILSIEKDL IPGNPTFITP TPKIDFEGLK LQPSRANRRW
PAAPFKRASV NSFGYGGSNA HVIVEEPKVL LPDMESTYVS SYQTEADLFA DDEEVAGGRL
QLLVLSANDE ASLRANATTL KNYLTNPNVK ISLGDLSHTL SERRSHHFHR GYLITDKASI
DENALVIGKK STNEPRVGFI FTGQGAQWPQ MGKAIIDTFP EARAVVLELD EFLQSSSLPP
SWSLLGELTE PREAEHLRKP EFSQPLVTAL QIALFDILQR WGISPRAVAG HSSGEIAAAY
AAGLLSKKAA IRAAYYRGQA AALAEKGTAD QNQQAFGMMA TGIGAEGITP YLQGLGQSVQ
IACYNSPSSL TLSGTVDALA KVQKQLSEDS IFARMLQVNL AYHSTFMREI SQGYTDLLNK
DFEHLPFKQD SVRMFSSVTG EQLAGPTDSE YWKSNMVCPV RFDAALSNML TASDAPDFLI
ELGPAGALKG PISQVLKSLE GTKAQYTSAM ARGAADMQSI FAVAGSLYVA GGKVDLAQVN
KVDGIKPKVV IDLPNYSWNH STKYWYESES SKDWRNRLFP PHDLLGSKVL GSPWRSPAFM
RSLNVQDLPW IADHKMGPDT VFPATGYISM AMEAIYQRSE ALHMLEGEKK VENPRYRLRD
VQFKKALVLP DNQSTRMSLT LSAYTGVGDW FEFKVSSLAG TTWIEHVRGL IRIDEDVPQV
ASAEEIKPLS HQVDASLWHK CMLDAGYSFG PKFLKQLQIE ARPGSRRSRS ILGLEVPESK
YPQSKYPMHP AAMDGCFQTC APSLWKGNRH AVNAVLVPAM IDSLTITSSK ADRGLSLTSA
AYVGLGRPTD NKNYMSNASV YDPETGNLLL RLSGLRYTRI DTGPSVYDAH TFSALISKPD
VSLLSSQSLE NLAEREQGLN DRSFGVATEL VRLAAHKKPA QRVLELNFVP GLSQSIWASA
IEGQDNIGKT YRQFVYRLTD PKALVEAGQQ YTSEKMEISL LDPEGMTLAE DEFDLVVVRL
SPAADNVEHV ATQLKKVVKE GGQVLFIRQR SVQNSEVIVN GEAEQFDNGS YADLLKSAGL
TFAGHVAFEE GNEFASLSLC RVQPEPDCTG KDVAIYHFVE PSTSALKVIT ALKARGWNVT
TYRAEEASTS PKRFLVLDEL DTALLPTLSP AHWDSLKILL SLDKRVLWVT NGSQTVISEP
NKAMIHGLGR TVRAEDPLVQ LTTLDVSASS TDATVDSVEV ILERLALPEV FHHVESEFIE
RNGLLHINRI QPDDQVNAVA SDSYEGSEPV EQSLHDSPNM IRLRCERVGT TDSLIYSEVS
PYELPLDDNK VEVEVYAAGL NYKDVVITMG IVPENEHILG LEGAGIVRRL GKNVHKVRKL
DIGQRVLVFK KGAFANRVHA EAERVYPIQD SMTFEETCTL ASSYLTGIHS LFNLADTKAG
SKVLIHSASG GLGLACIQLC QYVGAEVFAT CGNKEKRDFL VKHAGIPADH IFNSRDTSFG
AAIMAATNGY GVDTILNSLT GDLLDESWRC IAAEGTMVEL GKRDMLDRKG LSMEPFGRNA
SYRCFDMGHD IVSDAMINNL LKRLFALLEA GHVKPVHVAT TFGWDNVSGA MRYMRSANHI
GKIVISSGDK PIIVPVRPSR APLQLRGEAG YLLIGGLKGL CGSVAVNLAS LGAKHIVVMA
RSGYDDEVSQ RVITDLAALG CTITLGQGDV SKADDVRRVI KQSPVPIGGV IQGAMVLRDR
VFTDMSIEEY HAAVDCKVAG TWNIHNALIE ENMKVEFFTM LSSVSGVVGQ KGQANYAAAN
AFLDAFAIYR HNLGLAGNSV DLGAIQDVGY MSHHVDLLEN LSSDAWTPIN EALMLKIVEF
SLKQQLTPIS KASAGQLITS IAVPQRENSS LLRDARFSTL SFSDGEDVGA GSDGKDAGIQ
ALQLLVKNKA AVSAIHDAVI DVTVRQFTTM LSLSEPMEPA KAPSSYGLDS LAAVEFRNWV
RLELKAEVTT LDIISATSLE QLAQKIVARL TAV
