POXE_PENO1
ID POXE_PENO1 Reviewed; 4080 AA.
AC S7ZFK6;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 16-OCT-2013, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=Hybrid PKS-NRPS synthetase poxE {ECO:0000303|PubMed:28365998};
DE Short=PKS-NRPS {ECO:0000303|PubMed:28365998};
DE EC=2.3.1.- {ECO:0000269|PubMed:28365998};
DE EC=6.3.2.- {ECO:0000269|PubMed:28365998};
DE AltName: Full=Oxaleimides biosynthesis cluster protein E {ECO:0000303|PubMed:28365998};
GN Name=poxE {ECO:0000303|PubMed:28365998}; ORFNames=PDE_04017;
OS Penicillium oxalicum (strain 114-2 / CGMCC 5302) (Penicillium decumbens).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=933388;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=114-2 / CGMCC 5302;
RX PubMed=23383313; DOI=10.1371/journal.pone.0055185;
RA Liu G., Zhang L., Wei X., Zou G., Qin Y., Ma L., Li J., Zheng H., Wang S.,
RA Wang C., Xun L., Zhao G.-P., Zhou Z., Qu Y.;
RT "Genomic and secretomic analyses reveal unique features of the
RT lignocellulolytic enzyme system of Penicillium decumbens.";
RL PLoS ONE 8:E55185-E55185(2013).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, INDUCTION, AND PATHWAY.
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 [3]
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: Hybrid PKS-NRPS synthetase; part of the gene cluster that
CC 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: PoxE has the following domain architecture: KS-MAT-DH-MT-KR-
CC ACP-C-A-T-R. The PKS module (domains KS to ACP) is responsible for the
CC biosynthesis of the octaketide chain and catalyzes Claisen
CC condensations, as well as beta-keto processing and methylation. The
CC downstream NRPS module contains the condensation (C), adenylation (A),
CC and thiolation (T) domains and catalyzes the formation of the amide
CC linkage between the octaketide and the (S,E)-2-aminodec-4-enoic acid
CC produced by the polyketide synthase poxF. The bimodular assembly line
CC is terminated with a putative reductase (R) domain that facilitates
CC formation and release of the poxE product.
CC {ECO:0000269|PubMed:28365998}.
CC -!- DISRUPTION PHENOTYPE: Impairs the productin of oxaleimides.
CC {ECO:0000269|PubMed:28365998}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; KB644411; EPS29069.1; -; Genomic_DNA.
DR SMR; S7ZFK6; -.
DR STRING; 69781.S7ZFK6; -.
DR EnsemblFungi; EPS29069; EPS29069; PDE_04017.
DR eggNOG; KOG1178; Eukaryota.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_37_5_1; -.
DR OrthoDB; 19161at2759; -.
DR PhylomeDB; S7ZFK6; -.
DR Proteomes; UP000019376; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016874; F:ligase 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: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; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 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; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR013120; Far_NAD-bd.
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; 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; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 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; PF07993; NAD_binding_4; 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; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 2.
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; PS00455; AMP_BINDING; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 2: Evidence at transcript level;
KW Ligase; Methyltransferase; Multifunctional enzyme; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat;
KW Transferase.
FT CHAIN 1..4080
FT /note="Hybrid PKS-NRPS synthetase poxE"
FT /id="PRO_0000453754"
FT DOMAIN 2405..2481
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3593..3673
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 11..445
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 554..878
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 945..1243
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 1400..1585
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 2118..2292
FT /note="Ketoreductase (KR)domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 2399..2478
FT /note="Peptidyl carrier protein"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 2488..2569
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2607..3036
FT /note="Condensation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 3069..3478
FT /note="Adenylation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 3598..3670
FT /note="Thiolation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT REGION 3740..3959
FT /note="Reductase (RED) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:28365998"
FT COMPBIAS 2488..2506
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2513..2527
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2528..2565
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /note="For ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2441
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3633
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 4080 AA; 447845 MW; 4DC157BCC42F4E29 CRC64;
MAPSQAPREP IAIVGSGCRF PGESSSPSKL WELLQAPRDV QTEIPPTRFN PHGFYHPDNL
HHGTSNVRHS YLLTEDHRHF DAQFFGIKPA EAHCIDPQQR LLMETVYESL ESAGLRLEDL
RGSETAVYVG LMCGDYADIV LRDPESFPMY LSTGTARSIM SNRISYFFDW HGPSMTIDTA
CSSSLVAVHE AVQTLRLGRS RVAVAAGSNL CLSPEPYIAE SKLQMLSPTG RSRMWDIQAD
GYARGDGVAA VVLKTLSAAL ADGDHIECLI RETSVNQDGR TRGITMPSSE AQTRLIQDTY
ARAGLDPMKP QERCQYFEAH GTGTPTGDPL EAAAIRQAFF PGDNNQDRGC LFVGSIKTVV
GHTEGTAGLA GVLKASLALR NGIIPPNLLF NQLNPKIKPF YTNLEIATAA KPWPVLPAGV
PRRASVNSFG FGGTNAHAII EAYEPALTAP SKSTEPDIAF IPFVFSAASE SALRRMLELY
AQHLSKNPTI NARDLGWTLQ ARRSRFPFSI AVPGATTDQL RSNLETRLNS TDARQPLKIV
KQESRPENPR ILGVFTGQGA QWATMGRALY QSPKVRQIIQ ELDASLQALP IGERPSWTLA
SELTADASVS RIKAAEISQP MCTAVQVVLV QLLQSAGVVF DAVVGHSSGE IAAAYAAGFL
SGTDAIRIAY YRGLCARLAQ GAHGEKGAMM AVGTGVEDAL ELCAEPEFRG RMSVAAVNSS
ASVTLSGDAD AITQAKEILD EEKKFARVLV VDKAYHSHHM QACSGRYLSC LAKARIAVSA
PTDTKCVWYS TVRQGPVTEA DLADLTGPYW NDNMVSPVLF AQAVETALAA RGPFNMAVEV
GPHPALRGPA QQTVQDVLET SLPYTPTLQR GMNDVEAMAE CLGLLWQGLA PGFVDLSSYD
AFLSQGAVSR VIKDLPRYSW DHDRVFWYES RVSRATRQRI AASHPILGTR CPDGVEQEFR
WRNFLSLKEL PWLTGHRIQG QIIFPGAGYI SAAVDSARAM SSNESIQLVE LQELLIRQAI
VFEDENASVE ILVSITDVTH HSKDMVRAQF SFYSAVGKES TQMTLNASGR LVITYGPVRK
DALPVQRPSL VDMVDVPSER FYNALDPLGY SYTGRFRALK SMQRKLGIAT GLVTRQEAAD
LSSVTLDPAM LDAAIQAVLL AKSFPGDGEL WCSQVPKVIH RIAVNPTLCD PSGNGVESTF
PLDAVLTMMK ASDTQGDVDV YSADGQYTMI RMEGIHAVPL EATNADRDRP FFSGVVWGPA
APDSQTVNFD ATATPEEYEL AYVLERVATF YLRKIHLAFP MDHSARHEGP YVGLLNYATY
VTQQVASGYH RYTQPHWARD TVAVIKSESQ RFPNNIDLAV MHIIGEHMVD VISTRATILE
HLTKDNLLSR YYEQAMGIGH FSDYLASVVE QIVHRYPQMK VLEIGAGTGM ATKKVIQRVG
HSFGSYTFTD ISSGFFENAR EIFASHQDQM VYKVLDAEKD PVAQGFGEQS YDLIVASFVL
HATSHLETTL HNLRRLLKPG GYVVMLEVTN LEQSRLGYIF GSLPGWWLGA NDGRILSPCV
PTEEWDRLLK LTGFSGVDTF TSDADALPYP ASAIVSQAVD ETVDFLRNPL GTPSDFVNRA
TPVVLIGGAS SSVRVIRDVV KRHLDTRFDQ VQVVDRLSDF VAISPAVSNG LLTLNLSDLE
EPVFQNMTAD SLAALKLLYE RSNYVLWVTE DARAGNPHQN QSLGFGRSMM VEMPHVQSQF
LDLDRITETS SVASRIVDAA LRFVGVNMPD RGGDVASAGL LWSTEPEIAV IGGRELLPRI
KLNRSQNLRY NASRRAIAED VDMDQKSVQL VRNGNAYVLE QGSTSGFGNQ TPGYTRIRVD
VSSLKSLHLG RGNALYLVAG TVLATGEKVI GFADKNSSIV DIPPSWMSHR PDISMAALIL
SIIARLFSRA ILSSISPGGV LVVAEPDELL APVLEWQASQ QKIRVVFVTT QEDAPERPNW
VVLHSQVHVR SLPKLAPTEP VTILDLSTGE EPSALALKLR NSLHPASAFE RLTYWFSDHA
RRGEIHIPAE AMLTMYRPPM SPPASDSVIA SHSFPVTDVS QIPAARCPLA VVDWQSTSHV
PALIRPVDHY PMLKSNKTYW LVGLTGSLGL SLCAWMIHQG AQNVVLTSRN PKIDQIILQE
LRSLGARVEV YAGDVTNQES LRGVYDRICQ TLPPVAGVGQ GAMVLIDTMI KDMEIDAMQS
VLQPKVKGSI NLDELFSAER PLDFFIFFSS ATCVTGNIGQ SNYAAANMFM TGLAANRNRR
GLAGSVMNIG AIMGVGYVTR ETSEALQRNL LKSGHVWMSE QDFHTIFAEA ILAGTPGSDA
NVEITCGLRI TNASEEQRPL WSFNPRFQHL VVMEEQVEET YEQDKKGMSL KLQLREARTT
DEIYEVIKEC FIVKLQIMLG LDDAATNSIT SKAADDLGID SLNTVEIRSW FLKEMKVDIP
VLRILGGATI GEIIKFVLEK LPSDMTPSLG LSPPTGAASK ATSQPNPKPK VVVERRNVPR
LEKKIVHSAG SRTSSSVTGT SKSVSPARSM DTASSQTSEA ASPSIHTEEI TKPLKPLAPL
LKADVVSSNL GKVITPVEQT AALSVRKEPL SFGQSRFWFL KLYLEDQTTF NITCLLRMTG
PLSVDSLSRA VTAVGQRHEA LRTCFTVEDG QSPVQTILPE STLKLERQEY RTMADVNTAT
KKLTQHVYEM ESGRLMRVIL LSSAPNSSVH YVLVGYHHIN MDGVSLEVFL HDLEKAYRGQ
PLSSDLLQYP DYAAKQRQER NQGAWQDDLT FWKNEMVGSN LEIPLLPLAS VAIRKPLTQY
RHHRVEQRLD ARLGAQIRQL CQSIKATPSH FYLATFTTLL ARLTRTREIW VGMADANRIQ
AETADSIGNY LNLLALRMQY DPDQPFVASV QAARKKSYGA LAHSRIPFDV LLSELQVPRS
STHSPLFQVF MDYRHDVREK RMFGDCQLEG VEYEMGRTAY DIALDVVDTA DDGPLIIMGL
QESLYSPDTA QMLLNSFLEM VRAFAQDSKQ PGGHVSLFSA SDLEKALALG NGSVVASQWP
ATLSHRIDDM AKQYPQKLAL NDGDNLRLTF QQMSQRADSI ASALLSANVS RQQRVAVFQH
PSSDCICSIL AILRIGATYV PLDLRLELAR LGSIVQDCEP TVFLVDSHTQ SQAPDLMLTR
PAMTINIADL PRIAPFPVMN RAAAEDEAVI LYTSGSTGNP KGVPLTHENL RVNIEGNQAE
FQFGPDDCLL QQIAFSFDFS VWQIFMALAN GASLFIAPST HRGDPVALMD LVVREDITIT
GATPSEYRSW FQHGDLARLK TSQWKTAVSA GEAMTTNMIR DFQALNKSDL RLVNGYGPTE
ASMSSNKLVV PYLTNKDHPE EWMEKGAVVA GYTAPNYSIY IVDEAMNLLP IGLPGQILIG
GPGIASGYLN NKELSCIRFI NDKYASPEQR ACGWRWAHLT GDRGRIGADG RLRIEGRIEG
DTQVKLRGYR IDLQDVEAAM LKASPGAFKD LVVSLHQSTQ ALVAHVVFSQ HYPAHKHSQA
LEIKSLELPR YMWPARTVSI DQMPVTVHGK LDRKALQTMD LPAIEPMKQT STAHLNEAQA
QMVQLWEEVI SKDILAAHHI VAESDFFAVG GTSMLLVDLQ RQIKSWFKME IALAELFSAN
TLEKMALLIK PQEDIATPAA VDAAPPSSPS PLALTASLPP APTTINWSEE VQLPRVLREQ
TSSGTTVSVP EKTSGLRLVL TGATGFIGQA LLQQLTANPA ISTVHCIAVR DPSAIPAHEK
ILVHAGDLTH AALGLAPAEA QAIFREVDAV IHNGADVSFM KSYHSLRRTN VESTIALIQN
SLSRQIPFHY ISSSGIANLA GTTTFAEVSA ASFIPPTDGS QGYLATKWVS ERLLEEAHRE
FGLPVYIHRP SSVTGSNAPP LDLMDNLMTY ARRLKAVPMP ERSSWKGYLD FVPVEQVVRD
VTGDVLSAAG TVPSARASKV HYIHHLGRQV SLTGLHRYLE RETGAVYRVL KMGEWLEEAT
QVGMDALLRT YLESMDKEDV KVVFPRLVAG KRHASTVGVA KGVKIGESWL EKGKTLLFSW
