ESYN_FUSEQ
ID ESYN_FUSEQ Reviewed; 3131 AA.
AC Q00869;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 2.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Enniatin synthase {ECO:0000303|PubMed:8483420};
DE AltName: Full=Nonribosomal cyclopeptide synthetase ESYN1 {ECO:0000303|PubMed:7601090};
DE Includes:
DE RecName: Full=N-methylcyclopeptide synthetase {ECO:0000303|PubMed:7601090};
DE EC=6.3.2.-;
DE Includes:
DE RecName: Full=S-adenosyl-L-methionine-dependent N-methyltransferase {ECO:0000303|PubMed:7601090};
DE EC=2.1.1.-;
GN Name=ESYN1 {ECO:0000303|PubMed:7601090};
OS Fusarium equiseti (Fusarium scirpi).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Nectriaceae; Fusarium;
OC Fusarium incarnatum-equiseti species complex.
OX NCBI_TaxID=61235;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DOMAIN, AND PATHWAY.
RC STRAIN=Lambotte et Fautrey;
RX PubMed=8483420; DOI=10.1111/j.1365-2958.1993.tb01181.x;
RA Haese A., Schubert M., Herrmann M., Zocher R.;
RT "Molecular characterization of the enniatin synthetase gene encoding a
RT multifunctional enzyme catalysing N-methyldepsipeptide formation in
RT Fusarium scirpi.";
RL Mol. Microbiol. 7:905-914(1993).
RN [2]
RP SEQUENCE REVISION.
RA Zocher R.;
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 1011-1034; 1677-1695; 2029-2049; 2098-2106 AND
RP 2294-2299, FUNCTION, DOMAIN, AND PATHWAY.
RC STRAIN=Lambotte et Fautrey;
RX PubMed=7601090; DOI=10.1111/j.1432-1033.1995.0119i.x;
RA Pieper R., Haese A., Schroeder W., Zocher R.;
RT "Arrangement of catalytic sites in the multifunctional enzyme enniatin
RT synthetase.";
RL Eur. J. Biochem. 230:119-126(1995).
RN [4]
RP ACTIVITY REGULATION.
RC STRAIN=Lambotte et Fautrey;
RA Billich A., Zocher R.;
RT "N-methyltransferase function of the multifunctional enzyme enniatin
RT synthetase.";
RL Biochemistry 26:8417-8423(1987).
RN [5]
RP FUNCTION, MUTAGENESIS OF TYR-2106, DOMAIN, AND PATHWAY.
RX PubMed=10887181; DOI=10.1074/jbc.m002614200;
RA Hacker C., Glinski M., Hornbogen T., Doller A., Zocher R.;
RT "Mutational analysis of the N-methyltransferase domain of the
RT multifunctional enzyme enniatin synthetase.";
RL J. Biol. Chem. 275:30826-30832(2000).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=9170286; DOI=10.1021/np970031g;
RA McKee T.C., Bokesch H.R., McCormick J.L., Rashid M.A., Spielvogel D.,
RA Gustafson K.R., Alavanja M.M., Cardelline J.H. II, Boyd M.R.;
RT "Isolation and characterization of new anti-HIV and cytotoxic leads from
RT plants, marine, and microbial organisms.";
RL J. Nat. Prod. 60:431-438(1997).
RN [7]
RP BIOTECHNOLOGY.
RX PubMed=15707993; DOI=10.1016/j.bbrc.2005.01.075;
RA Hiraga K., Yamamoto S., Fukuda H., Hamanaka N., Oda K.;
RT "Enniatin has a new function as an inhibitor of Pdr5p, one of the ABC
RT transporters in Saccharomyces cerevisiae.";
RL Biochem. Biophys. Res. Commun. 328:1119-1125(2005).
RN [8]
RP BIOTECHNOLOGY.
RX PubMed=16562855; DOI=10.1021/np050487v;
RA Jayasinghe L., Abbas H.K., Jacob M.R., Herath W.H., Nanayakkara N.P.;
RT "N-Methyl-4-hydroxy-2-pyridinone analogues from Fusarium oxysporum.";
RL J. Nat. Prod. 69:439-442(2006).
RN [9]
RP BIOTECHNOLOGY.
RX PubMed=17326668; DOI=10.1021/tx600259t;
RA Dornetshuber R., Heffeter P., Kamyar M.R., Peterbauer T., Berger W.,
RA Lemmens-Gruber R.;
RT "Enniatin exerts p53-dependent cytostatic and p53-independent cytotoxic
RT activities against human cancer cells.";
RL Chem. Res. Toxicol. 20:465-473(2007).
CC -!- FUNCTION: Nonribosomal peptide synthetase that synthesizes enniatin by
CC coupling three D-hydroxycarboxylic acids and three L-amino acids via
CC amide and ester bonds in an alternating fashion (PubMed:7601090,
CC PubMed:10887181). Whereas ESYN1 can accept different amino acids as
CC precursors (L -valine, L-isoleucine or L-leucine), only one species of
CC D-hydroxycarboxylic acid can be found in natural enniatin isolates (D-
CC hydroxyisovaleric acid, D-Hiv) (PubMed:7601090, PubMed:10887181). D-Hiv
CC stems from L-valine deanimation by a valine aminotransferase to 2-keto-
CC isovaleric acid (2-Kiv), which becomes subsequently reduced by a keto-
CC isovaleric acid reductase (KivR) to D-Hiv (PubMed:7601090,
CC PubMed:10887181). Peptide bond formation and N-methylation of the amino
CC acid occur before three enzyme-bound dipeptidols are condensed to a
CC hexapeptidol (PubMed:7601090, PubMed:10887181).
CC {ECO:0000269|PubMed:10887181, ECO:0000269|PubMed:7601090}.
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000305};
CC Note=Binds 6 phosphopantetheines covalently. {ECO:0000305};
CC -!- ACTIVITY REGULATION: The N-methylation activity is inhibited by S-
CC adenosyl-L-homocysteine and sinefugin. {ECO:0000269|Ref.4}.
CC -!- PATHWAY: Antibiotic biosynthesis; enniatin biosynthesis.
CC {ECO:0000269|PubMed:10887181, ECO:0000269|PubMed:7601090,
CC ECO:0000269|PubMed:8483420}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC additional domains required for further modifications are also present
CC (Probable). Enniatin synthetase has the C1-A1-T1-C2-A2-MT-T2a-T2b-C3
CC domain organization (Probable). The precursors D-hydroxycarboxylic
CC acids and L-amino acids become activated at the A1 and the A2 domains.
CC N-methylation of the amino acid takes place at the MT-domain. The
CC building blocks are transferred from one module to another by means of
CC T-domains and are ultimately stored at the waiting position T2b.
CC Condensation of the building blocks and final cyclization and release
CC from the enzyme is catalyzed by the C-domains (Probable). {ECO:0000305,
CC ECO:0000305|PubMed:10887181, ECO:0000305|PubMed:8483420}.
CC -!- PTM: The N-terminus is blocked.
CC -!- BIOTECHNOLOGY: Enniatins have antimicrobial, antiviral and cytotoxic
CC properties (PubMed:9170286, PubMed:16562855, PubMed:17326668). The
CC bioactivity of enniatins can be linked to their inhibition of drug
CC efflux pumps (PubMed:15707993). {ECO:0000269|PubMed:15707993,
CC ECO:0000269|PubMed:16562855, ECO:0000269|PubMed:17326668,
CC ECO:0000269|PubMed:9170286}.
CC -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC {ECO:0000305}.
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DR EMBL; Z18755; CAA79245.2; -; Genomic_DNA.
DR PIR; S39842; S39842.
DR SMR; Q00869; -.
DR PRIDE; Q00869; -.
DR UniPathway; UPA00234; -.
DR GO; GO:0016881; F:acid-amino acid ligase activity; ISS:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0046585; P:enniatin biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0019184; P:nonribosomal peptide biosynthetic process; TAS:UniProtKB.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 3.
DR Gene3D; 3.40.50.12780; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR036736; ACP-like_sf.
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; IPR013216; Methyltransf_11.
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 Pfam; PF00501; AMP-binding; 2.
DR Pfam; PF00668; Condensation; 3.
DR Pfam; PF08241; Methyltransf_11; 1.
DR Pfam; PF00550; PP-binding; 3.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF47336; SSF47336; 3.
DR SUPFAM; SSF53335; SSF53335; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 2.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 3.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 3.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Ligase; Methyltransferase;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Repeat;
KW Transferase.
FT CHAIN 1..3131
FT /note="Enniatin synthase"
FT /id="PRO_0000180306"
FT DOMAIN 1010..1086
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2504..2578
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2598..2671
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 53..466
FT /note="Condensation 1"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255"
FT REGION 186..212
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 495..887
FT /note="Adenylation 1"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255"
FT REGION 1105..1534
FT /note="Condensation 2"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255"
FT REGION 1563..1960
FT /note="Adenylation 2"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255"
FT REGION 2021..2177
FT /note="S-adenosyl-L-methionine-dependent N-
FT methyltransferase"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255,
FT ECO:0000305|PubMed:10887181, ECO:0000305|PubMed:7601090,
FT ECO:0000305|PubMed:8483420"
FT REGION 2718..3123
FT /note="Condensation 3"
FT /evidence="ECO:0000250|UniProtKB:A0A0A1EA36, ECO:0000255"
FT MOD_RES 1047
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2538
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2632
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 2106
FT /note="Y->A,S,V: Reduces S-adenosyl-L-methionine binding."
FT /evidence="ECO:0000269|PubMed:10887181"
FT MUTAGEN 2106
FT /note="Y->F: Has minimal effect on S-adenosyl-L-methionine
FT binding."
FT /evidence="ECO:0000269|PubMed:10887181"
SQ SEQUENCE 3131 AA; 346499 MW; AD7663E91FAB67C4 CRC64;
MSLHTPSDGQ QDPALASKTL CEQISRALGL GQDKIENIFP GTPFQRDVID CAADDKQRAV
GHAVFEIPKD IDAARLAAAW KETVLHTPAL RTCTFTSKSG DVLQVVLRDS FVFSWMSGPS
VDLKEAVVQD EAAAALAGPR CNRFVLLEDP DTKERQLIWT FSHALVDSTF QERILRRVLK
AYKDANDEHP RQFETPDSSQ ATPEEDLQPN PSKMLKIPQA ADMDRAVEFW KDHLSGLKCF
CLPAFVLSSV YAHPDAKAEH RISYSSSAQQ KMSSATICRT ALAILLSRYT HSPEALFGIV
TEQTPLLEEQ LMLDGPTRTV VPIRVSCASE QSVSDIMSTI DSYDQTMRQF AHAGLRNIAS
AGDDESAACG FQTVLLVSDG DAQPASTWEI LKKTEEPEGF IPCTNRALLL SCQMTSSGAH
LTARYDQSII DAEQMARLLR QLGHLIQNLQ TSTDLPVEKV DMMTQEDWLE IERWNSDSID
AQDTLIHSEM LKWTSQSPNK AAVAAWDGEW TYAELDNVSS RLAQHINSID LGKEHAIVPI
YFEKSKWVVA SMLAVLKAGH AFTLIDPSDP PARTAQVVQQ TSATVALTSK LHRETVQSTV
GRCIVVDEEF VKSLPQSSEL SASVKAHDLA YVIFTSGSTG IPKGIMIEHR SFSSCAIKFG
PALGITSDTR ALQFGSHAFG ACILEIMTTL IHGGCVCIPS DDDRMNNVLE FINRTNVQLG
HATPSYMGTF QPEVVPGLKT LVLVGEQMSA SVNEVWAPRV QLLNGYGQSE SSSICCVAKI
SPGSSEPNNI GHAVGAHSWI VDPEDPNRLA PIGAVGELVI ESAGIARDYI VAPTQDKSPF
IKTAPTWYPA KQLPDGFKIY RTGDLACYAS DGSIVCLGRM DSQVKIRGQR VELGAVETHL
RQQMPDDMTI VVEAVKFSDS SSTTVLTAFL IGAGEKNSHI LDQRATREIN AKMEQVLPRH
SIPAFYISMN NLPQTATGKV DRRKLRIMGS KILSQKTHST PSQQSQAAIS SGTDTYTKLE
SIWITSLDLE PGSANMSATF FEMGGNSIIA IKMVNMARSN GIELKVSDIY QNPTLAGLKA
IVIGTSLPYS LIPKVTRQGP VSEQSYAQNR MWFLDQLSEG ASWYLIPFAV RMRGPVDVDA
LTRALLALEQ RHETLRTTFE NQDGVGVQII HDRLSKELQV IDALDGDEGG LKTLYKVETT
TFDITSEAGW SSTLIRLGKD DHILSIVMHH IISDGWSIDV LRRELIQLYA AALQGKDPSS
ALTPLPIQYS DFAVWQKQEA QAAEHERQLQ YWKKQLADSS PAKIPTDFPR PDLLSGDAGV
VPVAIDGELY QKLRGFCNKH NSTAFSILLA AFRAAHYRLT AVDDAVIGIP IANRNRWELE
NMIGFFVNTQ CMRIAVDETD TFESLVRQVR STTTAAFAHE DVPFERVVSA LQPGHRDLSR
TPLAQIMFAV HSQKDLGRFE LEGIQSEPIA SKAYTRFDVE FHLFQQADGL KGSCNFATDL
FKPETIQNVV SVFFQILRHG LDQPETCISV LPLTDGVEEL RRLDLLEIKR TNYPRDSSVV
DVFREQAAAN PEVIAVTDSS SRLTYAELDN KSELLSRWLR RRNLTPETLV SVLAPRSCET
IVAYVGILKA NLAYLPLDVR SPVTRMKDIL SSVSGNTIVL MGSGVEDPGF DLPQLELVRI
TDTFDETIED VQDSPQPSAT SLAYVVFTSG STGKPKGVMI EHRAIVRLVK SDNFPGFPSP
ARMSNVFNPA FDGAIWEINW MLLNGGTVVC IDYLTTLDGK ELAAVFAKER VNAAFFAPAM
LKLYLVDARE ALKNLDFLIV GGERFDTKEA VEAMPLVRGK IANIYGPTEA GIISTCYNIP
KDEAYTNGVP IGGSIYNSGA YVMDPNQQLV GLGVMGELVV TGDGVGRGYT NPELNKNRFI
DITIEGKTFK AYRTGDRMRA RVGDGLLEFF GRMDNQFKIR GNRIEAGEVE SAMLSLKNVL
NAAIVVRGGG EDEGPLEMVG FIVADDKNDT TEEEETGNQV EGWQDHFESG MYSDISTAVD
QSAIGNDFKG WTSMYDGKDI DKGEMQEWLD DAIHTLHNGQ IPRDVLEIGT GSGMILFNLN
PGLNSYVGLD PSKSAVEFVN RAVESSPKFA GKAKVHVGMA TDVNKLGEVH PDLVVFNSVV
QYFPTPEYLA EVIDGLIAIP SVKRIFLGDI RSYATNGHFL AARAIHTLGT NNNATKDRVR
QKIQELEDRE EEFLVEPAFF TTLKERRPDV VKHVEIIPKN MKATNELSAY RYTAVVHLRD
ETDEPVYHIE KDSWVDFEAK QMDKTALLDH LRLSKDAMSV AVSNITYAHT AFERRIVESL
DEDSKDDTKG TLDGAAWLSA VRSEAENRAS LTVPDILEIA KEAGFRVEVS AARQWSQSGA
LDAVFHHFPP SSTDRTLIQF PTDNELRSSL TLANRPLQKL QRRRAALQVR EKLQTLVPSY
MVPPNIVVLD TMPLNTNGKI DRKELTRRAR TLPKQQTAAP VPDFPISDIE ITLCEEATEV
FGMKVEISDH FFQLGGHSLL ATKLISRIQH RLHVRVTVKD VFDSPVFADL AVIIRQGLAM
QNPVAEGQDK QGWSSRVAPR TEVEKMLCEE FAAGLGVPVG ITDNFFDLGG HSLMATKLAV
RIGRRLIRHH SQGHLRLPCA FQLAKKLESS HSKSYEESGD DIQMADYTAF QLLDLEDPQD
FVQSQIRPQL DSCYGTIQDV YPSTQMQKAF LFDPTTGEPR GLVPFYIDFP SNADAETLTK
AIGALVDKLD MFRTVFLEAA GDLYQVVVEH LNLPIETIET EKNVNTATGD YLDVHGKDPV
RLGHPCIQFA ILKTASSVRV LLRMSHALYD GLSFEYIVRG LHVLYSGRNL PPPTQFARYM
QYAAHSREEG YPFWREVLQN APMTVLHDTN NGMSEQEMPA SKAVHLSEVV NVPAQAIRNS
TNTQATVFNT ACALVLAKES GSQDVVFGRI VSGRQGLPVV WQDIIGPCTN AVPVHARVDD
GNPQRIIRDL RDQYLRTLPF ESLGFEEIKR NCTDWPEELT NFSVCVTYHN FEYHPESEVD
NQKVEMGVLA KYVELSENEP LYDLAIAGEV EADGVNLKVT VVAKARLYNE ARIRHVLEEV
CKTFNGLNEA L
