MLFA_ASPKW
ID MLFA_ASPKW Reviewed; 5101 AA.
AC G7XQ31;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 25-JAN-2012, sequence version 1.
DT 03-AUG-2022, entry version 55.
DE RecName: Full=Malformin synthetase mlfA {ECO:0000303|PubMed:30560908};
DE EC=6.3.2.- {ECO:0000269|PubMed:30560908};
DE AltName: Full=Malformin biosynthesis cluster protein A {ECO:0000303|PubMed:30560908};
DE AltName: Full=Nonribosomal peptide synthetase mlfA {ECO:0000303|PubMed:30560908};
GN Name=mlfA {ECO:0000303|PubMed:30560908}; ORFNames=AKAW_07282;
OS Aspergillus kawachii (strain NBRC 4308) (White koji mold) (Aspergillus
OS awamori var. kawachi).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1033177;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NBRC 4308;
RX PubMed=22045919; DOI=10.1128/ec.05224-11;
RA Futagami T., Mori K., Yamashita A., Wada S., Kajiwara Y., Takashita H.,
RA Omori T., Takegawa K., Tashiro K., Kuhara S., Goto M.;
RT "Genome sequence of the white koji mold Aspergillus kawachii IFO 4308, used
RT for brewing the Japanese distilled spirit shochu.";
RL Eukaryot. Cell 10:1586-1587(2011).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=19876076; DOI=10.1038/ja.2009.100;
RA Kojima Y., Sunazuka T., Nagai K., Hirose T., Namatame M., Ishiyama A.,
RA Otoguro K., Omura S.;
RT "Solid-phase synthesis and biological activity of malformin C and its
RT derivatives.";
RL J. Antibiot. 62:681-686(2009).
RN [3]
RP BIOTECHNOLOGY.
RX PubMed=26540166; DOI=10.1371/journal.pone.0140069;
RA Wang J., Jiang Z., Lam W., Gullen E.A., Yu Z., Wei Y., Wang L., Zeiss C.,
RA Beck A., Cheng E.C., Wu C., Cheng Y.C., Zhang Y.;
RT "Study of malformin C, a fungal source cyclic pentapeptide, as an anti-
RT cancer drug.";
RL PLoS ONE 10:E0140069-E0140069(2015).
RN [4]
RP BIOTECHNOLOGY.
RX PubMed=26645406; DOI=10.1007/s00280-015-2915-4;
RA Liu Y., Wang M., Wang D., Li X., Wang W., Lou H., Yuan H.;
RT "Malformin A1 promotes cell death through induction of apoptosis, necrosis
RT and autophagy in prostate cancer cells.";
RL Cancer Chemother. Pharmacol. 77:63-75(2016).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=28713983; DOI=10.3892/ijo.2017.4070;
RA Park S.Y., Oh H.H., Park Y.L., Yu H.M., Myung D.S., Cho S.B., Lee W.S.,
RA Park D., Joo Y.E.;
RT "Malformin A1 treatment alters invasive and oncogenic phenotypes of human
RT colorectal cancer cells through stimulation of the p38 signaling pathway.";
RL Int. J. Oncol. 51:959-966(2017).
RN [6]
RP IDENTIFICATION, FUNCTION, AND PATHWAY.
RX PubMed=30560908; DOI=10.1038/s41598-018-36561-3;
RA Theobald S., Vesth T.C., Rendsvig J.K., Nielsen K.F., Riley R.,
RA de Abreu L.M., Salamov A., Frisvad J.C., Larsen T.O., Andersen M.R.,
RA Hoof J.B.;
RT "Uncovering secondary metabolite evolution and biosynthesis using gene
RT cluster networks and genetic dereplication.";
RL Sci. Rep. 8:17957-17957(2018).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of malformins, cyclic pentapeptides with
CC a disulfide bond between 2 consecutive cysteins, that show potential
CC anti-tumor as well as antimalarial and antitrypanosomal properties
CC (PubMed:30560908). The nonribosomal peptide synthetase mlfA is
CC responsible of the formation of the cyclic pentapeptide (Probable). The
CC malformin biosynthesis clusters in malformin-producing fungi also
CC contain enzymes involved in the formation of the disulfide bond between
CC the two consecutive cysteins within malformins, in addition to
CC additionnal tailoring enzymes such as methyltransferases or
CC oxidoreductases. They are also composed of up to 4 major facilitator
CC superfamily transporters, and transcription factors probably involved
CC in the regulation of the expression of those clusters (Probable).
CC {ECO:0000269|PubMed:30560908, ECO:0000305|PubMed:30560908}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:30560908}.
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 epimerase (E) domains (responsible for L- to D- amino acid conversion)
CC are present within the NRP synthetase. MlfA has the following
CC architecture: A-T-C-A-T-C-A-T-C-C-A-T-C, with the functions of the five
CC condensation domains during malformin biosynthesis being DL-joining
CC (epimerizing subtype), LL-joining, epimerization, DL-joining and
CC cyclizing domain, respectively. {ECO:0000305|PubMed:30560908}.
CC -!- BIOTECHNOLOGY: Malformins show anti-tumor properties against human
CC colorectal and prostate cancer cells by the inhibition of proliferation
CC and induction of apoptosis through the activation of the p38 signaling
CC pathway (PubMed:26540166, PubMed:26645406, PubMed:28713983). Malformin
CC C has also been shown to exhibit potent antimalarial and
CC antitrypanosomal properties (PubMed:19876076).
CC {ECO:0000269|PubMed:19876076, ECO:0000269|PubMed:26540166,
CC ECO:0000269|PubMed:26645406, ECO:0000269|PubMed:28713983}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; DF126466; GAA89168.1; -; Genomic_DNA.
DR SMR; G7XQ31; -.
DR STRING; 40384.G7XQ31; -.
DR VEuPathDB; FungiDB:AKAW_07282; -.
DR eggNOG; KOG1178; Eukaryota.
DR InParanoid; G7XQ31; -.
DR Proteomes; UP000006812; Unassembled WGS sequence.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 4.
DR Gene3D; 3.30.300.30; -; 4.
DR Gene3D; 3.30.559.10; -; 5.
DR Gene3D; 3.40.50.12780; -; 4.
DR InterPro; IPR010071; AA_adenyl_domain.
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; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR Pfam; PF00501; AMP-binding; 4.
DR Pfam; PF00668; Condensation; 5.
DR Pfam; PF00550; PP-binding; 4.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF47336; SSF47336; 4.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 4.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 4.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein.
FT CHAIN 1..5101
FT /note="Malformin synthetase mlfA"
FT /id="PRO_0000446432"
FT DOMAIN 757..830
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1854..1931
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3032..3108
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 4579..4655
FT /note="Carrier 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 225..616
FT /note="Adenylation 1"
FT /evidence="ECO:0000255"
FT REGION 868..1299
FT /note="Condensation 1"
FT /evidence="ECO:0000255"
FT REGION 1327..1716
FT /note="Adenylation 2"
FT /evidence="ECO:0000255"
FT REGION 1932..1961
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1994..2020
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2066..2481
FT /note="Condensation 2"
FT /evidence="ECO:0000255"
FT REGION 2504..2896
FT /note="Adenylation 3"
FT /evidence="ECO:0000255"
FT REGION 3125..3590
FT /note="Condensation 3"
FT /evidence="ECO:0000255"
FT REGION 3611..4030
FT /note="Condensation 4"
FT /evidence="ECO:0000255"
FT REGION 4055..4445
FT /note="Adenylation 4"
FT /evidence="ECO:0000255"
FT REGION 4712..5097
FT /note="Condensation 5"
FT /evidence="ECO:0000255"
FT COMPBIAS 1932..1955
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1994..2016
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 791
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1891
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3069
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 4616
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 5101 AA; 561810 MW; 976EEA82BA3D97F1 CRC64;
MSRFSCIFPT LTDGYVPNPD HTRAAGRRTY RIDLSGWKAP GSETESLILA AWGLVLSSYV
GTDEVAFYVV PTTGPDTTAL AELKVEGDMP RQSLTYAAHQ LLHPGLVGAG QVSGETANTI
ITFANDIESL FVTQTEESFL SLHVYRDEQG HISLSLTYYL SLLTDAQAAN VGTAMAQALA
EVGTCDNDKL VKDLSLMSPA HLEHIWRFNA DVPGIWEECF HDVIERHAAN RPHSLAVDAW
DTELTYTDLV REARLLAAYL QRRGVGPGSV VPISFERSGA ALVAMLAVSK AGGAFVSVPP
NLPAGRVDAI LEVIEAPFVV TWTKYESFWA ERLPTLPIDN YPKPAADATV EALGKPEDLF
YVIFTSGSTG RPKGCMLSHT NWLNGALRNA PSWKYGPESR VLQMLSHTFD MSLLEICTSL
GSGSCVCVPR PEEIETSISD AINRWQVNHV IMTPSLARAL RPDDVPGLKT MCLGGEAFPK
EIVTMWSERI NLWQFYGPSE CSINSSSWPI TRPDADPLNI GPPNSAACWV VDVHDYNKLV
PVGAIGELLV SGPIVGMGYL KNPVKTAEAF LEEVGFVAKD DPQFGGFRFY RTGDLVRWNS
DGTITFCGRA DTQVKLNGQR LELAEVEYQL GLEAGVQYAI AMAPQAGLCK NNLIAILTVK
GTSTGTQDTA ADEIPLLDRR DPIVQETVKK LRSQLQHALP RYMVPTIWAF VGRMPMSASG
KIDRVKLRDW VQRMSQETFD AITGRSLEAE EHAFGLSRLE QKIQLAWAEA LGLSAAEVGL
QQPFVALGGD SIKALDAVAR CRARQIKISM VHILSCEGVR EAASLAEVQE TPAQQVAEMA
VDYSNLWTRL SNDYDLDKLG VTQVEEVEDV FPCTTMQEGM FLGQIRRPGA YHMRFFHRVQ
LKGGCLPTVE RIQQAWASLV ERHPSLRTVF VDDLSPEAIY HSIVLRSVPM EVRMREVPRD
LSAEAALAIF TEELVPFRAN APLHRMLLLT CRGRVPYLML EISHVIMDGY ALSVFRREFI
RACSSSAPLP RGPDYRMFAN YHRTRQTDDS ARYWTDYLAD CVPCHIPTHA VSAPSDGPPE
WPRTLQRRDF GFENSAAFLQ RCKERQVTLA CAIRAAWALV LRAYTQSEDV CFGYVSSGRN
VPVPEVETIF GLCLSMQVCR ARLSEASTIA SLARKIQEDY VASLPFQHYP LAEAQRGLKQ
THGQGLFNTA ISMEWVPPSA EDEDALLDLE EIREQDDPTE YDIAISVDVH EGHIKLGFLY
WPDLTDFEIN HLAEALHGAM NCFASHPDEA LNTLSLLQAS DVCSALSDGP TLLPLEAVRG
NVVSMIDRWV TRQPEGAAID GWDGSMSYKE LHEQSSWVAR NLLHQGVRLG DRVLVCADRS
SRTVATILGI VRAGCVLVLS NPTDPEKRLQ WLAKKCNASL VVADPTYEER LATADAHVLS
TTSVCAPAAW DYEFPALDEH DLISILFKSG STGTPKGILM EHGALATSVF LGHGRTLRFS
RHTRMLHFAS LTFDAALAEI FTTLAHGGCI CVPCEEDRLS DVPGCISRFA VNTAMLTPSV
GRLLDPGALP TLQTLIMVGE PMSRLDVERF APVLDLYNGA GPTETSIMVT IAGPMKPTDE
PVNLGYAVAG VRLWVTEAEN PNRLAPLGAV GELIVEGRLV TSGYLDDQAR TQEAFLPTLP
WLPSQHALYR TGDLVRYVDD GSLRYMGRKD TQVKLRGQRI ELQEVEYHLR KSLQQAQIVV
EMVVPAGKMR AQASLVAFVS GLTAADVESS SACNLEGTIP ISQIVLPKSA FQALEEVLPR
HMIPSVYYAL DTIPLSVNGK ADRRRLREMG SLLLASSAAH KNNIEGMSKS VKWTPTLELE
RTLLGLWAAT LGLEAETIHG DDSFFELGGD SVSAMKLVAT ARDKYKLSLS VPQMFRYPTV
CQLAAEVGEP AGQSASSASS TTEEGFTFST PDDSSTNDGV DDDFLQLATA QLAQLAQEKG
KKVDIAALLK QLQGGSSSNK TPSVSSSSSS SSSSKRKKNA AKAESLAEAA APIPVQFSLL
DGGADALDKV RAQAVEHCKI THDDIEDIYP ATALQEGMMA LTARTPGVYT TTLTGDLSEQ
VDIARLQYAW GKAAEAHPIL RTRIILTDNN TAVQVVQRAK GLPWDTYSLR EDNVLPDLTS
NMTSGSPLLR LAVVHRQSQP RMLLVAIHHA LYDGWSMPLL KQAVEDAYHG RDLRPQPFTP
FIKHLIAGKP AAQDFWTTHL DNFVGGVFPK LPSIYHQIQP TERRTRSMTL PTAAPKAQYT
MATKIQAAWA VTVSRYVEAN DIVFGTVSTG RSAPVPAIDR MVGPTVTTVP VRISLGGQAD
RVLSLLQRVQ EDSWNKLDHE HLGLQHIRRL GESAAAACNF QTLLVIQPRE QPDTKYRSTL
LSGLQDVAEL EGVDTYPLML VCEPDGASLN LTAVFDRAVL DGATLDRMLA HWELVLTQMW
NEPNMAVIDI DAVSCSDKET LMRWNTGETI TEGCAHNAVC EWSRRTPHAP AVCAWDGEWT
YKELERYSSL IASQISAHGL SSGDFVALYH EKSRWTAAGI LAVFKAGAIL ITLDPAHPTD
RIKDILDQAR PRLILTSQSL LDVARNLDTP VLSVQFAASQ PLPEEWSSLP TICPTLAAYA
PFTSGSTGRP KGIPLDHRGL AASTASIARS CLLRPASRVL HFASFAFDAS MMEHLIAWHA
GGCLCIPDET ARQTDLAKCI RDFNVTWAFL TPSCLRLITP DDVPSLQALG LGGESMTSED
ITIWSPRLRQ IVQLYGPAEC CIVAALTEVT KPSENRLIGR PNACRCWVVD PQNPDRLAPI
GAVGELLIEG ITVGRGYIND PDRTTPAFIR PPKWLQTLYP DDQEPKRLYR TGDLVRYAGV
DGKLAFIGRR DGQLKLHGQR IELADVEAHL RSLIPGMQKM VVEMVHSADN QNPFLAAFLE
EISTSQKPKE REIGLLHPSQ SQCALDVKAI DSALSRTVPQ YMIPSMYLHI SRLPLSASGK
LDRRHLREMV AELPRQSLNE YAAGSGLGVP DRPVTSQEHE MQAIWARVLS LDPNTFGVND
DFFRIGGDSI SGMQVSTKCN AAGIHITSAD LFRHRTIEQL ICHLNTIRTT DSASVLLPTE
PVNEWVALAP IQHLFFEVAP EGPNHFNQSL LLRTSRRVSV EELAGGLDVL IGRHSMLRAR
FCRKDSGQWF QQVKSLDSEP ASAFYRLAAH NHITRESLPT LFTAAQMALS IEDGPLLTVD
LVELEDGSQL VYLAAHHLII DLVSWRILHG DLEEYLQTGS LSSATGSVPF LTWTQLQAEY
SAEHLTPARA LPGFQEANDD FDFMRYWGIS SESNTFGQTS TSRFALDRTV TDILFGSANK
VMDTRPVEIL EAALWYSCNQ ALPDHPGPSI YVEGHGREPW TDSIDVSGTV GWFTIMSPLV
STPWHHLSRK SMRDFVDVLS YIKDQRRRIP ANGWAYFTSR YLNDEGRVAY GRTKPVMEVL
FNYMGQYQEM KREDAILQLA GDDIQSGTGA SDIAGNVPRF SLIDVTAFTA NGCLTFEFTF
PQLIQQDARL EQCIKECEHT LVAAASSLSA EGPRKTLTDF PLMSALTYDQ LSQCLNHTLP
SMGLRAQDVW NIYPCSPVQR GMLLAQLRDR QAYQQRFKFQ VMSRGPTEQL SLEKVKDAWT
EVINRHDILR TLLLPVSDHS HFDQVVMVPG SLQHLVRGDA MDANPTEGLP HTINITSDST
GAIICEWNVS HALVDAMSIA FIQREVNQAL EGSLGQHQNL PQYVEYIKWL TLQDNTEAQA
YWQNHLNGVE PCLFPKLTSS PDKVNPEATI SAIRATWSRD VRMDELCHKH AITLTNLFHI
VWAIVLGAYV GTDEVCFGYT ALGRDVPVHR VETLVGPLVN VLATTVRHQE DETILNALLT
HQAHLTNSLQ HQHYALADVY ASLGLVGSQL FNTIVSLQDT SHFDAPDEQR TRLEMLPAND
VSEYDVALNI GVDKSTIQLV CSYQTVSLSA EQADALLRTA FHVLDEILRD PTQRFCELEV
ISPKCKEHLV KWNAGMLAPT HEYIHEKIQG QCRIHNSRQA VCAWDGMFTY AEVDDLSSRL
AARLIRMGVT SEDIIPIYSP KSRWMVIAIL GVLKAGAAFT LLEISHPMAR LRVICNQIKA
PMLIAPASHA VPAANLAPIL VVLDNITSLA EERPVSLPAV DIPPAREALA YLIFTSGSTG
NPKGVMVTHQ NLCSNASIIT TSVNMTSDSR VLQFASHAFD GCLWEILGAL LAGACLIIPS
ESENKEDLTG CIERMGVTWA FLTPSVARIL KPETLPSLCN LVLGGEPIAA SDLEMWRGHV
QVVCAYGPTE TTILASTTSP STFPRDGKDI GTPTSSSLWI VDTRNYQTLV PLGATGELLI
EGPNVSQGYL GDPEKTNNAF PDAPRWLSQL RKSPTRLYRT GDLVRFDTST GTIRFVGRKD
NQIKFHGQRI ELGEIEYHAQ FAFSSASTVI VDLITPEQPR QPYIVAFVHQ LDAANETTDT
NDTLLLPSSE VFRADALAAQ NKMHKRLPHY MVPAVFLPLH RLPLSVTGKA DRKRLRQCAL
ALSSPELSAY RATASTKRMP STAAERKMQE LVATVLGRDP TEIGMDDSFF YLGGDSVQAM
RLVAEGRQQG LTLSLRAIFD SPCLGDLSDQ AKSLIEDNQR ASTASRGNLR YDCDRIDKIV
VTNSLNKADV VDVLPTTSFQ RHWLDAQLKS YIVVDIPGPI DPARLLRAMH RVVEAHPILR
VSFVPYETTT VQVILRTAVA ITNVDLSTAT VEELCRRDVD AQMAPGVPYL RVIIATQDKA
GHKLIMRLSH AQYDAVSLSL LMNDLSHAYA NDTHPLPSSH FPRFNDYITY QQAQRADPTA
TTFWRHLLQD VPLTHLNLQP AESSASNGTP ITLSRDIDIA VFPSLPSDIT IATMVKAAWS
LALAQKTNSL AVIFGQVVHG RAIALPGVEG IVGPCANITP VVARLGLETT GLELMQALQD
QHHSAMSYES VDLDDALAYA NDSQAGRKGL QTIVQHQNNV MVDDMELSLG EVKCGVDFRA
VDHLPKEVWV YSSVDEKRPG MLEVKIMSST LVLGEEFAEE LMGLLVEKIV GLLRHPESVC
V