ID EUPA_PHOSX Reviewed; 2682 AA.
AC A0A4P8GHJ1;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 31-JUL-2019, sequence version 1.
DT 27-NOV-2024, entry version 23.
DE RecName: Full=3-methylorcinaldehyde synthase {ECO:0000303|PubMed:30980906};
DE Short=MOS {ECO:0000303|PubMed:30980906};
DE EC=2.3.1.- {ECO:0000305|PubMed:30980906};
DE AltName: Full=Eupenifeldin biosynthesis cluster protein A {ECO:0000303|PubMed:30980906};
DE AltName: Full=Non-reducing polyketide synthase eupA {ECO:0000303|PubMed:30980906};
DE Short=NR-PKS eupA {ECO:0000303|PubMed:30980906};
GN Name=eupA {ECO:0000303|PubMed:30980906}; ORFNames=gme12632;
OS Phoma sp.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Didymellaceae; Phoma.
OX NCBI_TaxID=1707701;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=XZ068 / CGMCC No. 10481;
RX PubMed=30980906; DOI=10.1016/j.fgb.2019.04.004;
RA Zhai Y., Li Y., Zhang J., Zhang Y., Ren F., Zhang X., Liu G., Liu X.,
RA Che Y.;
RT "Identification of the gene cluster for bistropolone-humulene meroterpenoid
RT biosynthesis in Phoma sp.";
RL Fungal Genet. Biol. 129:7-15(2019).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=8360103; DOI=10.7164/antibiotics.46.1082;
RA Mayerl F., Gao Q., Huang S., Klohr S.E., Matson J.A., Gustavson D.R.,
RA Pirnik D.M., Berry R.L., Fairchild C., Rose W.C.;
RT "Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium
RT brefeldianum.";
RL J. Antibiot. 46:1082-1088(1993).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=18095654; DOI=10.1021/np070513k;
RA Ayers S., Zink D.L., Powell J.S., Brown C.M., Grund A., Bills G.F.,
RA Platas G., Thompson D., Singh S.B.;
RT "Noreupenifeldin, a tropolone from an unidentified ascomycete.";
RL J. Nat. Prod. 71:457-459(2008).
RN [4]
RP BIOTECHNOLOGY.
RX DOI=10.1016/j.phytol.2008.09.008;
RA Bunyapaiboonsri T., Veeranondha S., Boonruangprapa T., Somrithipol S.;
RT "Ramiferin, a bisphenol-sesquiterpene from the fungus Kionochaeta ramifera
RT BCC 7585.";
RL Phytochem. Lett. 1:204-206(2008).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of eupenifeldin, a bistropolone
CC meroterpenoid that acts as an antitumor agent (PubMed:30980906). The
CC first step of eupenifeldin biosynthesis is the biosynthesis of 3-
CC methylorcinaldehyde performed by the non-reducing polyketide synthase
CC eupA (PubMed:30980906). Oxidative dearomatization of 3-
CC methylorcinaldehyde likely catalyzed by the FAD-dependent monooxygenase
CC eupB is followed by oxidative ring expansion by the 2-oxoglutarate-
CC dependent dioxygenase eupC to provide the first tropolone metabolite,
CC tropolone stipitaldehyde (Probable). In parallel, generation of
CC sesquiterpene alpha-humulene from farnesylpyrophosphate (FPP) is
CC catalyzed by the terpene cyclase eupE (PubMed:30980906). The cytochrome
CC P450 monooxygenase eupD then hydroxylates humulene to humulenol
CC (PubMed:30980906). The putative Diels-Alderase eupF probably catalyzes
CC the formation of the tropolone-humulene skeleton by linking humulenol
CC and the polyketide moiety (Probable). The short-chain
CC dehydrogenase/reductase eupG and the flavin-dependent monooxygenase
CC eupH are also essential for eupenifeldin biosynthesis and are likely
CC the additional decorating enzymes of the tropolone-humulene skeleton to
CC produce final eupenifeldin or derivatives (Probable).
CC {ECO:0000269|PubMed:30980906, ECO:0000305|PubMed:30980906}.
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:30980906}.
CC -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC repeated decarboxylative condensation to elongate the polyketide
CC backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC transfers the extender unit malonyl-CoA; a product template (PT) domain
CC that controls the immediate cyclization regioselectivity of the
CC reactive polyketide backbone; an acyl-carrier protein (ACP) that serves
CC as the tether of the growing and completed polyketide via its
CC phosphopantetheinyl arm; a C-methylation (C-Met) domain; and a C-
CC terminal reductase (R) domain (By similarity). Methylation occurs
CC during the processive construction of the carbon backbone, directly
CC after the second extension at the triketide stage (By similarity). The
CC C-terminal R domain is involved in a reductive release mechanism,
CC reducing the thiolester intermediate to the observed aldehyde and
CC concomitantly releasing the free holo-ACP thiol (By similarity).
CC {ECO:0000250|UniProtKB:A5PHD6, ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of eupenifeldin.
CC {ECO:0000269|PubMed:30980906}.
CC -!- BIOTECHNOLOGY: Eupenifeldin is a bistropolone-humulene meroterpenoid
CC first discovered as an antitumor and anti-leukemia agent
CC (PubMed:8360103). This metabolite shows also anthelmintic activity
CC against the parasitic worm Hemonchus contortus, anti-malarial activity
CC as well as antifungal activity (PubMed:18095654, Ref.4).
CC {ECO:0000269|PubMed:18095654, ECO:0000269|PubMed:8360103,
CC ECO:0000269|Ref.4}.
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; MK400120; QCO93110.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A4P8GHJ1; -.
DR SMR; A0A4P8GHJ1; -.
DR UniPathway; UPA00213; -.
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: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 GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR CDD; cd02440; AdoMet_MTases; 1.
DR CDD; cd00833; PKS; 1.
DR Gene3D; 3.30.70.3290; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 1.10.1200.10; ACP-like; 1.
DR Gene3D; 3.40.366.10; Malonyl-Coenzyme A Acyl Carrier Protein, domain 2; 2.
DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR Gene3D; 3.10.129.110; Polyketide synthase dehydratase; 1.
DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase_dom.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
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; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR049900; PKS_mFAS_DH.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR050444; Polyketide_Synthase.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR PANTHER; PTHR45681:SF6; CARRIER DOMAIN-CONTAINING PROTEIN; 1.
DR PANTHER; PTHR45681; POLYKETIDE SYNTHASE 44-RELATED; 1.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF18558; HTH_51; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF16073; SAT; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; ACP-like; 1.
DR SUPFAM; SSF52151; FabD/lysophospholipase-like; 1.
DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR SUPFAM; SSF55048; Probable ACP-binding domain of malonyl-CoA ACP transacylase; 1.
DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
DR SUPFAM; SSF53901; Thiolase-like; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00606; KS3_1; 1.
DR PROSITE; PS52004; KS3_2; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
DR PROSITE; PS52019; PKS_MFAS_DH; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2682
FT /note="3-methylorcinaldehyde synthase"
FT /id="PRO_0000449149"
FT DOMAIN 401..826
FT /note="Ketosynthase family 3 (KS3)"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348"
FT DOMAIN 1339..1651
FT /note="PKS/mFAS DH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01363"
FT DOMAIN 1723..1797
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 111..272
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 947..1237
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1339..1468
FT /note="N-terminal hotdog fold"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01363"
FT REGION 1367..1649
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1496..1651
FT /note="C-terminal hotdog fold"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01363"
FT REGION 2021..2211
FT /note="Methyltransferase domain"
FT /evidence="ECO:0000255"
FT REGION 2303..2548
FT /note="NADPH-binding (R) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 154
FT /note="Nucleophile; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 272
FT /note="Proton donor/acceptor; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 573
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348"
FT ACT_SITE 708
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348"
FT ACT_SITE 749
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01348"
FT ACT_SITE 1371
FT /note="Proton acceptor; for dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01363"
FT ACT_SITE 1555
FT /note="Proton donor; for dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01363"
FT MOD_RES 1757
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2682 AA; 295551 MW; 7ABE910BE4C84775 CRC64;
MQTEEWKMAN QDNNKPQRDS ERCVFLFGSL SLSFDASAFA QVRKAIANDE RNSWLVNAAR
QLPQDLETIL SGLPSLNNSN TRARKQLADL HNAIIGGRPL DTPFPLPNTV LIPLVVIEQL
SQYADFARQK GVERSGTPDG WPAIEADTKS LGLCTGNLAA FATSSARSWG DFQKYGAAAV
RLGLLVGLVI DSQDEAFDSR RWRSLSVAWS GSQGGEELQR ILPEFDETYV SVYYDACRST
ITTPVSSLPT LVHRLKAAGL GVTEITLYGA FHSAARNSAV LEQLTVFCDS HADFQLSTSA
ASVAALQAND NTDHKDIIRK QGALHAKALR RILVEPAQWF DALAAVLGEE GERARVVSFG
SERSVPLSLA MRSNVRVVHA TDTHDGNRGT NADGGERMWA ESDIAVIGMA CKVAGAEGVE
EFWELLVEGH SQHRDISASE RFSFDDTAFR TASDSNMQRK WYANLVDGHD QFDHRFFKKS
ARESAAMDPQ QRQLLQVAYQ AAEQAGCFTR TNSVCDGNVG CFVGVCLSDY ESNVGCHPAN
AFTATGNLQG FIAGKVSHFL GWTGPALTID TACSSSLVAV HQACASILAG ECNSALAGGT
HIMTTAGWFQ NLAAGAFVSP TGQCKPFDAA ADGYCRGEGV GAVVLKKLSQ AIADGDRVLG
VIGATAVQQN QNCTPIFVPN VPSLSALFTT VTAKAHVKPA SVSVVEAHGT GTAVGDPAEW
ASIRQTLGGL NRPPERPLMV SSTKGLVGHL ECTSGIISLI KVLLMVQKRM LPPQASFDTL
NPVLNAQPSD HMFVPRRAQP WDAEFRVALI NNYGASGSNA SMIVMQPPTF DTVAPIHLAA
AVRSPDCRYP FWLSGLDSSS LRRRAKALRR FLSRGLGPAS SLAPSLASIS YNLAHQGDRA
LDQRITFTAA SVTELDQHLA ACEDGSDNKP AAPASTAASK QTVVMCFGGQ VSTHIGLDPH
VYNSVGLLRQ HLDNVDTIIQ SLGYTTIFPA IFQRVPLADT VHLQTMLFAM QFACAQAWID
SGLRPTVLVG HSFGELTALC VSGALSLVDA VKMIARRAAI VRDAWGIDRG TMMAVEGDLY
EVEQLLVDVN SSISPAVPIS IACYNGPRSF TLAGSTDTIN EVDARLCAQP GRSIKSRRLN
VTNAFHSALV DPLLHRLEES CEDLTFRRPV LYLERALDST SSGPEWSARS VAEHMRNPVY
FHHALQRIVQ IDPSSSFVFV EAGTNSSITA MTSRALDNKI IKGTSTFHGL SIANCDDGWN
KLTDSIMSLW KAGLNVQHWA HHQRQRRYQA DIEPLLLPPY QFDPNARHWM DLKPLPRQLP
ALIEEATKTE ADKKPEGLLT FVGFQDSSTQ MQAQFQINTN TEEYKSLLLG HMTIQTAPIC
PATMQISFVI EAIVTIRHEL QTEQEPQIQD VQYRSPVCAN LSRKTWIEIK DENERGLAWR
FEVFSTESHS GPRTIHTTGK IKFTNARDAT LQRQLMQFER LFGHHRATDL LKSAEVDEVL
ANRSIYLIFS EIVDYGEEYR GLQKFASKGH ESAGHVVRRH SHDRKTPRFD AHLADTFCQL
GGIWINCMTE RSQDDIYLAN SIDQWIRSPH NAGAAGSTVE PSKEYHVYAT HHRPSDKLSL
TDVFVFDVKA GKLVEVILGI AYVKIPKLSM QKMLTRLTGS EWLNNTPATS MNQAPVSAPN
PATRPSIVDL PSAVTQVPVL LPQGVKPSAE IRPSEPPSRS LLENITERVK AVVADLSGVE
VTEIGDECDL ADLGIDSLAG MQMVHEIEGA LHVTLPEKEI LLVVTMRDLM KVVTGVVEVD
FEATDSLSSD NDLPSIATSS EGERVATNLT TPAPQSDVDK DEHEAFESND LRLPAAVVLE
AFKETRELTD EHVLGVGQAS YVSEALPLQT ELSISLTLEA FEALGAGLRN AGPGEQLFRI
VHDEEHARFV DYMYDMLEIE TQIIKVDRGI ITRTAVPFPE RSSTVVYAEL RRRFPDQRAA
DELTYYAGTH LMQVLSGETT GVKLIFGTTE GRELVSTFYG EWPLNQVMYT QMEDFFTRLA
SKLPATNDNK PLRILEMGAG TGGTTKRLVP LLARLQIPVE YTFTDLAPSF VRAARNKWEK
LYPWMRFRVH DIEKAPGEDL VNTQHFVLAS NAIHATRSIR ESTLNVRKFL RSDGYLLMGE
MTRTPYWVDI IFGLFEGWWL FDDGRRHALT HESRWETDLQ SAGYGHVYWT EGTRPESEIE
KLILAAASLT NLAGSDFVQS ERNPITKRHQ FDNEVSGGCA EREKLIMEYV CDSTQDFAKT
FKVPMSSIPR SLHHKSKGKW IVVTGATGGL GAHLVAKAAV RSDVERVVCL NRRSKQNALE
RQMHALRKQG ISLDSECLAK LDVHVTELAQ PSSLGLPNEL YNLLLDNVTH IVHNAWLMNS
KWTVKRFEPQ IRIMKHMIHF ARDISLRHTE SDPVTFIFVS SIATVGFHPL LAKSPIVPED
RVSIDSVLPT GYGEAKYICE RMLDTSLHRY PSRFRAAAVR LGQIAGSSLN GYWNPMEHVS
FLIKSSQTLR ALPNLPGSLG WTPADAIADS LLDICTQPGD VALHPLYHID NPVRQNWDEM
LAVLADVLNI SQGASGIVPF DEWLRRVRDW PHTEDNASDG KNPAYVLVDF LEDHFVRMSC
GGLLLGTRKA REHSETLACV GPVDAQAIKL YVRSWKDMGF LD
//
