MLFA_ASPVC
ID MLFA_ASPVC Reviewed; 5104 AA.
AC A0A319BQC1;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 10-OCT-2018, sequence version 1.
DT 25-MAY-2022, entry version 22.
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=BO88DRAFT_464700;
OS Aspergillus vadensis (strain CBS 113365 / IMI 142717 / IBT 24658).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1448311;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CBS 113365 / IMI 142717 / IBT 24658;
RX PubMed=30349117; DOI=10.1038/s41588-018-0246-1;
RA Vesth T.C., Nybo J.L., Theobald S., Frisvad J.C., Larsen T.O.,
RA Nielsen K.F., Hoof J.B., Brandl J., Salamov A., Riley R., Gladden J.M.,
RA Phatale P., Nielsen M.T., Lyhne E.K., Kogle M.E., Strasser K.,
RA McDonnell E., Barry K., Clum A., Chen C., LaButti K., Haridas S., Nolan M.,
RA Sandor L., Kuo A., Lipzen A., Hainaut M., Drula E., Tsang A.,
RA Magnuson J.K., Henrissat B., Wiebenga A., Simmons B.A., Maekelae M.R.,
RA de Vries R.P., Grigoriev I.V., Mortensen U.H., Baker S.E., Andersen M.R.;
RT "Investigation of inter- and intraspecies variation through genome
RT sequencing of Aspergillus section Nigri.";
RL Nat. Genet. 50:1688-1695(2018).
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}.
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; KZ821628; PYH67913.1; -; Genomic_DNA.
DR SMR; A0A319BQC1; -.
DR Proteomes; UP000248405; 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; 3.
DR PROSITE; PS50075; CARRIER; 4.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Repeat.
FT CHAIN 1..5104
FT /note="Malformin synthetase mlfA"
FT /id="PRO_0000446440"
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 4578..4654
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 1928..1961
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1998..2025
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..4029
FT /note="Condensation 4"
FT /evidence="ECO:0000255"
FT REGION 4054..4444
FT /note="Adenylation 4"
FT /evidence="ECO:0000255"
FT REGION 4691..5018
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 1998..2014
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 4615
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 5104 AA; 561642 MW; 0C3DB0F40E91F29D CRC64;
MSRFSCIFPT LTDGYVPNPD HTRAAGRRTY TIDLSGWKAP GSEKESHILA AWALVLSSYV
GTDEVAFYVV PVTGPDTTAL AELKVEGDMS RQSLTCAAEQ LLHPALVGAG QVSRETANTI
ITFANDIESL FVTQTEESFL SLQVYRNEQG HISLSLVYYL SLLTDAQAAN VGTAMAQALA
EVGTCDNDRL IKDLNLMSPA HLEHIWRFNA NVPGIWEECF HDVIERHAVN RPHSLAVDAW
DTKLTYADLV REARLLAAYL QQRGVRPGSV VPISFERSGA ALVAMLAVSK AGGAFVSVPP
NLPAGRLDAI LDVIEAPFVV TWTKYESFWA ERLPTLPIDN YPKPAADATV EALGKPEDLF
YVIFTSGSTG RPKGCMLSHS NWLNGALRNA PSWKYGPQSR VLQMLSHTFD MSLLEICTSL
GSGACVCVPR TEEIETSISD AINRWQVNHV IMTPSLARAL RPDDVPGLKT MCLGGEAFPK
EIVTMWSERI NLWQFYGPSE CSINSSSRPI TRPDADPLNI GPPNSAACWV VDVQDYNKLV
PVGAIGELLV SGPIVGMGYL KNPVKTAEAF LDEVEFVAKD DPQFGGFRFY RTGDLVRWNS
DGTITFCGRA DTQVKLNGQR LELAEVEYQL GLEAGVQYAI AMAPQAGLCK NNLLAILTVK
GTSTGNQDTA ADEIPLLDRR DPIVQETVKK LRSQLQHALP RYMVPTIWAF VGRLPMSASG
KIDRVQLRDW VQKMSQETFD AITGRSLEAE GHVLGLSRLE QEIQLAWAEA LGLSAAEVGL
QQPFVALGGD SIKALDAVAR CRACQIKISM VHILSCEGVR EAASLAEVQE TPAQQVAEMA
VDYSNLWTRL SNDYDLGKLG VTRVDEVEDV FPCTTMQEGM FLGQIRRPGA YHMRFFHRVQ
LKGGCLPTVE RIQQAWASLV ERHPSLRTVF VDDLSPEAIY HSIVLRSVPM ELRMREVPRD
LSAEAALAMF TEELVPFRAN APLHRMLLLT CRGRVPYLML EISHVIMDGY ALSVFRREFI
RACSSSPPLP RGPDYRMFAN YHRTRQTDES TGYWTNYLAD CVPCHIPTHA VSAPSDAPPE
WPRTLQRRDF GVDNSAAFLQ RCKERQVTLA CAIRAAWALV LRAYTQSKDV CFGYVSSGRN
VPVPEVEAIF GLCLSMQVCR ARLSEASTIA SLARRIQEDY VASLPFQHYP LAEAQRGLKQ
THGQGLFNTA ISMEWVPPSV EDEDALLDLE EIREQDDPTE YDIAISVDVH EGHIKLGFLY
WPNLTDFEIT HLAEALRGAM NCFAFQPDGA LNTLSLLQAS DVCSALADGP TLLPLEAVRG
NAVSMIDRWV TRQPEGAAID GWDGSLSYKE LHEQSSWVAR NLLHQGVQLG DRVLVCADRS
SRTVAIVLGI VRAGCVLVLS NPTDPEKRLQ WLAKKCDAAL VVADPTYEER FATSGSRILS
TTSVCAPAAW DYEFPALDEH DLISILFTSG STGTPKGILM EHGALATSVL LGHGRTLRFS
RHTRMLHFAS LTFDAALAEI FTTLAHGGCI CVPCEEDRLS DVPGCISSFA VNTAMLTPSV
GRLLDPGALP TLKTLIMVGE PMSRLDVERF APVLDLYNGA GPTETSIMVT IAGPMKPTDE
PVNLGFAVAG VRLWVTEAEN PNRLAPLGAV GELIVEGRLV TRGYLDDPAR TQEAFLPTLP
WLPSQHALYR TGDLVRYAED GSLRYMGRKD TQVKLRGQRI ELQEVEYHLR KSLQQAQIVV
EMVVPAGKMR AQASLVAFVS GLTAADVESS SACNFGGTIP ISQIVLSKST FQALGEVLPR
HMIPSVYYAL DTIPLSLNGK ADRRRLREMG SALLASSAAH KNTIEGMRES VKWTPASELE
RTLLELWAAT LALDAETIHG DDSFFELGGD SVSAMKLVAT ARDKFKLSLS VPQMFRYPTI
RQLAAEFGGP AGQSASSASS TTEERFTFST PDDSSTNDGV DDDFLQLATA QLAQLAQEKG
KKVDIAALLK QLQGGSFTNK TPSVSSSSSS SSSSEKKKKA AKVDSQAEAA APVPVQFSLL
DGGAEFLEKV REQAVEQCKV PHEDIEDIYP ATPLQEGMMA LTARTPGVYT TTLTCDLSEE
VDLARLHYAW GKAAEAHPIL RTRLILTDNN TAVQVVQRAE ELPWDTYSLH DGDVLPDLTS
NMTFGSPLLR LAVVHRQNQP RMLLVAIHHA LYDGWSMPLL KQAVEDAYHG RDLRPQPFTP
FIEYVIVGKQ AAQDFWTTHL DSFAGGVFPN FPSIDYQINP TERRTRSMTL PTVTPRAQYT
MATKIQAAWA VTVSRYAEAN DIVFGTVSTG RSAPVPAIDR MVGPTITTVP VRISLSNQAE
RVNSLLQRVQ DDSWKKMDHG HLGLQHIRRL GESAAAACSF QTLLVIQPRE QPDTKYRSTL
LSGLQDVAEL KGVDTYPLML VCEPDGARLH LTAVFDPAVL NGITLERMLA HWELVLIQLW
NEPDMAVIEL DTVSYSDKEA LMRWNTGETI PNGCAHDAVS EWSVRTPHAP AVCAWDGEWT
YEELERCSSL IASQILAHGV SSGDFVALYH EKSRWAAAGI LAVFKAGAIL ITLDPAHPTD
RIKDILDQAR PRLILTSQSL LDVARNFETP LLSVQFAASK PLPEGWSSLP TISSTQAAYT
PFTSGSTGRP KGIPLDHRGL AASTASIARS CLLRPASRVL HFASFAFDAS MMEHLIAWHA
GGCLCIPDDT ARQTDLAKCI RGFNVTWAFL TPSCLRLITP DDVPSLQALG LGGESMTSED
ITIWGPRLRQ IVQLYGPAEC CIVAALTPVT KPSENRLIGR PNACRCWVVD SQNLDRMAPI
GAVGELVIEG ITVGRGYIND PDRTNRAFIR HPKWLQTLYP DDQESKRLYR TGDLVRYAGV
DGKLVFIGRR DGQLKLHGQR IELADVEAHL RPLIPGTQKV VVEMVHSADN QNPILAAFLE
EMSASQKPTE REVGLLHPSQ SQCDQDVKAI DSALSRTVPQ YMIPSMYLHI SRLPLSASGK
LNRRHLREMV AELPRQRLNE YAAGSGLSAP DRPVTSQERE MRAIWARVLS LDPNTIGVND
DFFRIGGDSI SGMQVATKCN AAGIHITSAD LFRHRNIEQL ICHLNTIRTT NCASVSLPTE
PVDKWVALAP IQQLFFEVAP EGPNHFNQSL LLHTSRRVSV EELARGLDIL VGRHSMLRAR
FCRKDSGQWF QQVKSLDYEP ASGLYRLAAH NQITRESLPT LFTAAQMALS IQDGPLLNVD
LVELEDGSQL VYLVAHHLII DLVSWRILHG ELEEYLQTGS LSSATGSVPF LTWSQLQAQY
SAEDLTPARA LPDFQEANDD FDVTRYWGIS SELNTFGQTS ISRFTLDRTV TDILFGNANK
VMDTRPVEIL QAALWYSCNQ ALTDRPRPSI YVEGHGREPW TDSINVSGTV GWFTTMSPLV
STPWDHLSRK PMRDFVDALS YIKDQRRRIP ANGWAYFTSR YLNDEGRIAY GRTKPVVEFL
FNYMGQYQEM NRDDAILQLA GDDIQSGTGA SDIADNVPRF SLIDVSAFTA NGCLTFEFIF
PELLQQDARL EQCIKECERT LVAAASSLSE EGPRKTLTDF PLMSALTYDQ LSQCLNHALP
SIGLRAQDVL NIYPCSPVQQ GMLLAQLRDR QAYQQRFRFR IKSQGPTDQL TLKKVKDAWT
QVINRHDILR TLLLPVSDHS HFDQVVMVPG SLQHLVRISG TDANPTKDLS HTINITSDSS
GTIICEWNVS HALVDAMSIA VIQREVDQEL EGALGQHQAP PQYVDYIQWL SLKDNTEAQA
YWQRYLKGVE PCLFPKLTSS SEVNPEGTIS AIRATWTRDA RMDELCHKHA ITLTNIFHIV
WAVVLGAYVG TDEVCFGYTT LGRDVPVDGV ETMVGPLVNV LATTVHLQQD RSILNALLTH
QSHLTNSLQH QHHALADVYS SLGLVGSQLF NTIVSLQDMS HFDAPDEQRT RLEMLPANDV
SEYNVTLNIG VDQSSIQLVC SYQSASLSAE HANALLRTAS HVLREILRDP TQEFCELEVI
SPECKEQLVK WNAGMLAPTD EYIHEKIQGQ CRIHSSREAV CAWDGTFTYA EIDYLSSRLA
ARLISMGVTS EDIIPIYSPK SRWTVIAILG VLKTGAAFML LETSHPVARL QAICDQVKTD
MIITPASHAV SAANLAPILV VLDNITSSTQ EKSDPLPAVG IPPAGEALAY LIFTSGSTGN
PKGVMITHEN LCSNASIITT SVNMTSDSRV LQFASHAFDG CILELLGALI AGACLIIPSE
SENKEDLAGC IERMDVTWAL LTPSVARILK PETLPRLSNL VLGGEPIAAS DLDMWRGHVQ
VVCAYGPTET TIVASTTSPS TFPADGKDIG LPNGSSLWIV DRWNYHKLSP LGATGELLIE
GPNVSQGYLG DPEKTSNAFP DAPRWLSRLR KSPTRLYRTG DLARFDTSTG TIRFVGRKDN
QIKFHGQRIE LGEIEHHAQL AFSSASTVIV DLITPEQPQQ PYIVAFVHQP DANTEATGTI
DTILLPPSES FRADALAAQN KMHKRLPHYM VPAVFLPLHR LPLSATGKAD RKRLRQCALA
LSSSELSAYR ATASTKRMPS TAAERKMQDL VATVLGRGPA EIGMDDSFFY LGGDSVQAMR
LVAEGRQQGL ALSLRAIFDS PCLGDLSDQA RSLIEDNQRI STASSAGLRD NCDQIDKIVA
TNSLNKTDVA DVLPTTSFQR HWLDGQLKSY IVVDIPGPID PARLFRAMHR VVEAHPILRV
LFVPYETTTL QVILRTAAAI INADLSTTTV EDICRQDADA QVAPGVPYLR VILATQGQAD
HKIIMRLSHA QYDAVSLSLL MKDLSHAYAN DTHPLPSSQF PRFNDYITYQ QAQRADPMAT
TFWRNLLQDV PLTYLNLQPA EPSTSNGTPI TLTRDIYIAA FPSLPNGITT ATAVKAAWSL
VLAQKSDSAA VIFGQVVHGR AIALPGVEGI VGPCANITPV VARLGLQTTG LDLMQSLQDQ
HRSAMPYEMV DLDDALAYTK KSEAGRKGLQ TIVQHQNNVM VDDMEFSLGE VKCGVDVRAV
DHVPKEVWVY SSVNEKRPGM LEVKIMSSTL VIGEEVAEEL IGLLVEKIMG LLRHPEGVCL
NGPC
