POXF_PENOX
ID POXF_PENOX Reviewed; 2527 AA.
AC A0A1W5T1T1;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2017, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=Highly reducing polyketide synthase poxF {ECO:0000303|PubMed:28365998};
DE Short=HR-PKS poxF {ECO:0000303|PubMed:28365998};
DE EC=2.3.1.- {ECO:0000269|PubMed:28365998};
DE AltName: Full=Oxaleimides biosynthesis cluster protein F {ECO:0000303|PubMed:28365998};
GN Name=poxF {ECO:0000303|PubMed:28365998};
OS Penicillium oxalicum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=69781;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE,
RP INDUCTION, AND PATHWAY.
RC STRAIN=K85;
RX PubMed=28365998; DOI=10.1021/jacs.7b02432;
RA Sato M., Dander J.E., Sato C., Hung Y.S., Gao S.S., Tang M.C., Hang L.,
RA Winter J.M., Garg N.K., Watanabe K., Tang Y.;
RT "Collaborative Biosynthesis of Maleimide- and Succinimide-Containing
RT Natural Products by Fungal Polyketide Megasynthases.";
RL J. Am. Chem. Soc. 139:5317-5320(2017).
RN [2]
RP FUNCTION.
RX PubMed=32039410; DOI=10.1039/c9cc09590j;
RA Hantke V., Skellam E.J., Cox R.J.;
RT "Evidence for enzyme catalysed intramolecular [4+2] Diels-Alder cyclization
RT during the biosynthesis of pyrichalasin H.";
RL Chem. Commun. (Camb.) 56:2925-2928(2020).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of oxaleimides, cytotoxic compounds
CC containing an unusual disubstituted succinimide moiety
CC (PubMed:28365998). The first step of the pathway is provided by the HR-
CC PKS poxF that serves in a new mode of collaborative biosynthesis with
CC the PKS-NRPS poxE, by providing the olefin containing amino acid
CC substrate via the synthesis of an ACP-bound dec-4-enoate
CC (PubMed:28365998). The cytochrome P450 monooxygenase poxM-catalyzed
CC oxidation at the alpha-position creates the enzyme-bound 2-hydroxydec-
CC 4-enoyl-ACP thioester, which may be prone to spontaneous hydrolysis to
CC yield 2-hydroxydec-4-enoic acid due to increased electrophilicity of
CC the carbonyl (PubMed:28365998). 2-hydroxydec-4-enoic acid can then be
CC further oxidized by poxM to yield the alpha-ketoacid 2-oxodec-4-
CC enoicacid, which is reductively aminated by the aminotransferase poxL
CC to yield (S,E)-2-aminodec-4-enoic acid (PubMed:28365998). The Hybrid
CC PKS-NRPS synthetase poxE then performs condensation between the
CC octaketide product of its PKS modules and the amino group of (S,E)-2-
CC aminodec-4-enoic acid which is activated and incorporated by the
CC adenylation domain (PubMed:28365998). The resulting aminoacyl product
CC can be cyclized by the Diels-Alderase PoxQ and reductively released by
CC the reductive (R) domain of poxE to yield an aldehyde intermediate
CC (PubMed:28365998) (Probable). The released aldehyde is then substrate
CC for a Knoevenagel condensation by the hydrolyase poxO followed by an
CC oxidation at the 5-position of the pyrrolidone ring (PubMed:28365998).
CC The presence of the olefin from the amino acid building block allows
CC for migration of the substituted allyl group to occur
CC (PubMed:28365998). This allylic transposition reaction takes place in a
CC conjugate addition, semipinacol-like fashion to yield a succinimide
CC intermediate (PubMed:28365998). Iterative two-electron oxidations of
CC the C7 methyl of the succinimide intermediate to the carboxylic acid
CC can be catalyzed by one of two remaining cytochrome P450
CC monooxygenasess poxC or poxD to yield oxaleimide A (PubMed:28365998).
CC Subsequent oxidation yields the maleimide scaffold oxaleimide I
CC (PubMed:28365998). Both oxaleimide A and oxaleimide I can undergo
CC oxidative modifications in the decalin ring to yield the series of
CC products oxaleimides B to H (PubMed:28365998).
CC {ECO:0000269|PubMed:28365998, ECO:0000305|PubMed:32039410}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:28365998}.
CC -!- INDUCTION: Expression is positively regulated by the oxaleimides
CC biosynthesis cluster-specific transcription factor poxB.
CC {ECO:0000269|PubMed:28365998}.
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:28365998}.
CC -!- DISRUPTION PHENOTYPE: Impairs the productin of oxaleimides.
CC {ECO:0000269|PubMed:28365998}.
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DR EMBL; KY764295; ARF05980.1; -; Genomic_DNA.
DR SMR; A0A1W5T1T1; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
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; 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; 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; 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; 2.
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.
PE 2: Evidence at transcript level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2527
FT /note="Highly reducing polyketide synthase poxF"
FT /id="PRO_0000453752"
FT DOMAIN 2445..2522
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 23..448
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 560..882
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 951..1243
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1406..1587
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1823..2137
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2162..2339
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 193
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2482
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2527 AA; 273303 MW; F80A5682FE7F59FD CRC64;
MIAPVNAGDT DASEPGDLGV MPIAIIGMAC RFPGDASNPE KLWNLCAKGK SAWSPIPESR
FHAESWYHPD KGHLGTSYVK GAHFLTEDIS RFDAAFFNCT AESASTMDPE VRMQLETVYE
ALESAGLPLD QVAGSRTGVY AGTCFRDNHD SLMRDPDTLA RFFLTGNGAA MIANRISHFF
DLRGPSLMVD TGCSTTLTLL HLACQSVRAG ESEMAIVGGS NVLLNPDMFI AGSNLSLLSE
AGRCFAFDSR AAGYGRGDGI ASIVIKPLAA ALRDGDPVRA VIRNSAANQD GKTATLTSPS
QDAQEELMRE CYDMAGLDPR DTSYVEAHGT GTQVGDTIEA HAIGHVFGAG RSSESPLVIG
SVKTNIGHTE AASGLAGVIK VVMAMEKRAI PPHMNFESPN EKISLEGLKL KIPLSLQEWP
SPLLQRASIN NFGYGGANAH VIVESPQSML LPLTPSSSEM GNTPNPKKRS RVFLLSAKDP
AAARSMGENL YDYVATTLEN SRENEEQILD QLAFTLGQRR TRFAWTTAWS GSSLADVHAR
LGSARSTAER STRAPRVGMV FTGQGAQWFA MGRELFSAYP VFYDTMHEID ACLKNMGATW
SAVEELQRDA KESRINQVTF SLPLSVAIQL ALVDLLRSWG IRPAGVTGHS SGEVGAAYAA
GAITLAGAMA IVYTRGDLTS QFQKLLDRRG GMVAVGLGRE EAEKALAEVQ SGTAVIACVN
SPSSVTISGD ECAVEEVEAM LTARGVFARR LRVEAAYHSH HMLPLAEAYR VLLSRFLEPN
TEFDSTVVYS SPTTGDRMTS AADIAHPDHW VRNMVQPVEF LNSLRNLCSG AAPARTSTST
AVDMLVEVGP HGALAGPIRQ TLALPELKDA GITYASCLSR GQDAVQTIHQ LICTLLQAGY
PVDLEAVNFP YGRSDVQVLT NLPPYPWNHE TSYWAEPRRN KELRARTVAP HDLLGVPAAG
STPTTPAWRH VVRPRDIPWV RDHIVQGAIV YPGAGYVSMV VEALRQLQTP DNPSHGYQLQ
DVQIRNPLIL EDTAEGVDVQ LSLHPCGDRV RHAQGWYEFL IQSVNQTGDL WTLHCEGLCC
TPSPAQGTGW AGPPAPVNAP SFTVPASAWR ILNPADTYKT LHEVGVCHGP IFQNLMSAQS
APGHSQSVFQ VADSAATMPQ GYQQSHVIHP ITLDAVFQAV YHNLPAGGTQ QRTAMIPTSI
QNLYISAKLI TSPGHQFRAD STLMKISGQG FESSVRVINN AGTDEANEPP TPVLTLDGLF
CQSLGSSAVV LTPDDKLCYT SVWAPDFDFL QPEHLLRKAE GAHQHSFSEL QAAAVVFIND
ALQEFENEQV VAAEHQSYWD WMKGVVDQAR PTLDLAGVTA QYMAALTEDL KQGVDGRLLC
RFGERLPEIL SGLVPAKEIL RDFLVEDQAE WSSVSEYLEP FMSSLMKLHG HKRPRATVLE
IGTGNVASTR MFAKALTRND TQLFARYDVT APSTGLVEVA SKALRDDTRA ECKVLDLDTP
AGDQGFTRAS YDLLILSASA LLAAEDVVQS LTSLRALLAP GGKCILWGPT LGDSALQTIV
RLLPRWSGVI NATPTWQRLL AKAGFEPSNF QLEEGLNSSG YQGEVVIATA KADTTIYSAV
KVVLVSGTSP PEEWQQTLQH SLPADVVSGI SVVSSLEDVD VEDKVCLILE EFVQPILENP
SEEQFYDLQR VLGSSRATVW VSRGAQGDAE DPRGSLHQGL LRTLRCENIL RQYVSVDLDP
NAPVWSSSSA TQIAWILSNM LITSSFHLPE TEYAIRNSVV QISRVYGDEQ EAQLVGTTKP
QNPELRPWST PGQNIRLGVA TPGLLNSLVF TEDPTIEETL PDDWVEIEPR AFGLNFRDIM
VALGQLDETR MGFECSGVIT RVGQSAQAAG FCPGQGVYAF IIGYFATKVR IPFTSVASIP
AGMDFATAAS IPLVFITAYH ALVDLARLQR DETVLIHSGT GGVGQAAIML AQSIGADIFV
TVGSEDKREF LMRQYGIPSS RIFSSRNPSF AQHIMSETDG KGVDVVLNSL AGPLLRETWR
CVGMFGRFIE IGKRDIEQNS MVEMGPFVRS TLFASLDLIT LGEQRGKEVQ RIFAAINELL
ADGEIRPVGP ITRFGIGEVE KAFRTMQTGK HMGKIVLEPR PGDQVRVLTA GPRPAELSPD
DTYLLVGGVG GIGKSLCQLL VDRGARNLLV LSRNAARITP ETQQWLDVLQ ATGARVVLES
CDVTQRAQLQ AVFEKYSSEL PPIRGVIQAA MVLKDGIFES MTHEDYLAAL KPKVQGTFNL
HTLLPTDLRF FILLSSISGF GGNAGQANYA AGGSYQDALA RHRAGRGLPA VSIDLGMVSS
VGVVAGTQHV ADHLEKLGLR AVSEQEVWAL VESAIRHPIR TPETCHIVTG LPGGFVRSDS
PVCWNRDARF AILEQKDFSS SGLASTSNPG AGLKERLSAV TTPAEVTTLI QSALITKLAE
MFSRSPEEID PSLPLAHFGV DSLVAVELRN WSVATVQADC SIFDVMHAVS VTGLAGQMAK
KSRFVKL
