MLFA_ASPSB
ID MLFA_ASPSB Reviewed; 5099 AA.
AC A0A319DV72;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 10-OCT-2018, sequence version 1.
DT 23-FEB-2022, entry version 11.
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=BO78DRAFT_455717;
OS Aspergillus sclerotiicarbonarius (strain CBS 121057 / IBT 28362).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1448318;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CBS 121057 / IBT 28362;
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}.
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DR EMBL; KZ826410; PYI01631.1; -; Genomic_DNA.
DR SMR; A0A319DV72; -.
DR STRING; 1448318.A0A319DV72; -.
DR Proteomes; UP000248423; 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; Reference proteome; Repeat.
FT CHAIN 1..5099
FT /note="Malformin synthetase mlfA"
FT /id="PRO_0000446438"
FT DOMAIN 756..829
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1857..1934
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 4581..4657
FT /note="Carrier 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 224..615
FT /note="Adenylation 1"
FT /evidence="ECO:0000255"
FT REGION 867..1297
FT /note="Condensation 1"
FT /evidence="ECO:0000255"
FT REGION 1325..1717
FT /note="Adenylation 2"
FT /evidence="ECO:0000255"
FT REGION 1995..2040
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2067..2482
FT /note="Condensation 2"
FT /evidence="ECO:0000255"
FT REGION 2505..2897
FT /note="Adenylation 3"
FT /evidence="ECO:0000255"
FT REGION 3125..3589
FT /note="Condensation 3"
FT /evidence="ECO:0000255"
FT REGION 3610..4033
FT /note="Condensation 4"
FT /evidence="ECO:0000255"
FT REGION 4058..4446
FT /note="Adenylation 4"
FT /evidence="ECO:0000255"
FT REGION 4696..5017
FT /note="Condensation 5"
FT /evidence="ECO:0000255"
FT COMPBIAS 1995..2019
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 790
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1894
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 4618
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 5099 AA; 560492 MW; 82A26FBC16BCB3A8 CRC64;
MGRFSCIFPS LTDGYIPDPA HCRAAGRRVY EIDLGGWGPL PDRPDAHLVA AWALILSSYV
GTDEVAFYVV PARGPDATAL CELKVNGSLP RRSLTDDAWQ LLHPLPLGPG QVSSETANTI
ITFAEDIDPL FITQAEEAFL TLHVRNTSPG NVALHLGYHL SLFTDAQAAN VGTAMAQVLT
SLAGDPDELV RDVDHMSRTH LDQIWHFNAN VPSTWQECFH DVVQRHAADR PHSLAIDAWD
GRLTYAELVG KATPLARHMQ ERGVRPGVVV PISFERSAGA LIAMLAVSKA GGAFVSVPTS
LPPGRLDAIL EVIEAPFVLT RSTHQSFWAG RLPALIIDNY PKPASTAVVE TLAKADDLFY
VIFTSGSTGR PKGCMLSHSN WLNGALRNAP NWKYGPNSRV LQMLNHTFDM SLLEICTSLG
SGACVCIPPA DEVEAGLAGA INRWQVNHVI MTPSLARALR PGDVPGLRTM CLGGEAFPRE
IVTMWSECIH LFQFYGPSEC SINSSTRAIT GVDADPLNIG PPNSAACWVS DIQDHNKLVP
IGAIGELLVS GPIVGMGYLR NPVKTAEAFI DHVGFIPMDD PKFAGFRLYK TGDLVRWNSD
GTLTFCGRAD TQVKLNGQRL ELAEVEYQLG LEADVQLAIA LVPQVGRCKN NLIAILTVRG
AATSSRGVTA GEIPLLNRQD PIVQQAVKRL RAQLQQALPR YMVPTIWAFV GHMPMSASGK
IDRVRVRGWV EEMSQETFDA ITGRSFEADD HLLGLTHLEN EIQLAWAEAL GLSAAEVGLH
QPFVALGGDS IKALDAVGRC RARQVDITMV STLSCEGVRE AASLAKVRDS PTQRVVEMAV
DYSDLWDCLS SDYDLAKLGI GNADEVEDVF PCTSMQEGMF LGQIRRPGAY HMRFFHRVQL
KGGGLPTVER IQTAWSSLVA RHPSLRTIFV DDLSPEAIYH SVVLRNVPVD TTTREVPRDL
SPEDALSMFT QELVPFRPNA PLHRLRLFTC RGRVSYFMLE ISHVIMDGYA LSVFRREFIQ
ACSTPASVPR GPDYRMFANY HRTRQTADSA AYWTAYLKDA APCHIPTYDQ AMAADGLDYP
RTLLRRDFSY QTSGTFLQRC KERQVTLACA IRATWALVLR AYTQSQDVCF GYVSSGRNVP
VPDVETIFGL CLSMQVCRAR VGESRTLVDL ARRIQEDYVE SLPYQHYPLA EVQRGLKQTR
RQALFNTAIS MEWVPPAGDD EDALIDLEEI REQDDPTEYD IAISVDVHAG CIKLGFLYWP
TLTEFEITHL AQAMQGAMDC FALQPDGPVD SLTLLKPGDL SSALVGWPDL LPLEAVRGNV
MSMIDRWVNR QPDTLAIDGW DESLTYHQLQ QQSSWVARNL LHRGVHQGDR ILVCMDRSSR
TVVTILGIVR SGAVLVLSNP ADPAKRLQWL TQKCNAAMIV ADPQYRDRFE APGNPSVTVV
DAPSVCTPAA WDYLFPVLDG QDPVSILFTS GSTGTPKGIV MHHGSLATSV LLGHGRTLRF
SRQTRMLHFA SLTFDAALAE IFTTLAHGGC MCIPSEDDRL SDVPGCIARF KVNTAMLTPS
VGRILDPAAL PTLRTLVLVG EPMSRLDVER FAPALDLYNG AGPTETSIMV TIAGPMQPTD
DPLNLGHAVA GVRLWVTETE APNRLAPLGA VGELVVEGSL VTQGYLDDPV RTQEAFLSKL
AWLPSHNPLY RTGDLVRYVA DGSFRYMGRK DTQVKLRGQR IELQEVEYHL RCSWPHAQVV
VEMVIPDGRT RSQAALVAFV SGLTPEDAHF LFNGALISAE APGIAQAVLS EKTTQALSEA
LPRHMVPSIY LALETIPLSV NGKADRRRLR DLGASWLASS AFHPGPECLQ TPTAEWARAP
ELERTLVELW ATTLSIEPGA IRGDDSFFEL GGDSVSAMKL VATARDKYKL SLSVPQVFRY
PTIRQIATQC EGIAVQLASS ASSTTEEGFT FSTPDESSTN EGLDGEFWQL ASAQLADLAR
EKGKTLDVAA ILKRMQQESS SSPAPSVSSS SSSSSAPKPL LAQPEPPTNL RDSVPEPFSL
IGGGPSAVEQ ICQQAMEQCQ IPRESIEDIY PATPLQEGMM ALMAKTPGVY TTTLRCELSN
QVDCARLQSA WDQASEAHPI LRTRIVLTND HRAMQVVQHG NRLPWDVYSL RDSDNLPDLT
SQMTLGSPLL RLAEIRQAGG QGRLLLVTIH HALYDGWSFP LVKQAVEDAY SGQALKSQAF
TPFIAYLNEG RLAAEQFWAD HLESFAGGAF PCLPTVDHRI RPTARLTRKL SLPVSAGHQY
TLATKIQAAW AVTVSRYDDE TDVVFGTVST GRAAPVPGID RVAGPTITTI PVRVSLQDRA
QRVGPFLQKV QEDGWRSLDH EHLGLQHIRR LGDSAAAACR LQTLLVLQPR QQPPAEPSSA
ILAGLQDMAE LEGLDTYPLM LVCEPDGADV HLIAIFDPVV LHEAILARMV THWEHVLTQL
WTEPDIAVVD LEALSPGDKK VLMRWNGASQ LPDGCVHESV HQWRLSTPHA PAVCAWDGDW
TYEELDNLSS ALAHHLTLHG VSHGTSVALY HEKSRWAAVG LLAVFKAGGI LVTLDPAHPV
DRLREILGQV QARVILSSQE HEATAKALGT LVLTVEEVAT QPEPELFRPV GPITSSQCAF
TPFTSGSTGR PKGIPLEHRG MVATIASMAE RCLLTTTSRV LQFASFAFDA SVMEHLLAWY
AGGCLCVPSE FDRQANLGEV IRDLRVNWAF LTPSCLRLIT PDDVPCLEGM GLGGEPVLPE
HITTWAPRLR QLVQMYGPAE CSFVTVLTEV TQASENRLIG SPSACRCWVI DPMDPDRLMP
LGAIGELVIE GLAVGRGYIN EPQRTAEAFI APPPWLQTLY PDDGQPRRLY RTGDLVRYAG
DDGRLTFVGR KDGQLKLHGQ RIELGDVETH LRPLIPATQG IAVEMIVCAD DQNPLLAAFI
EVSQDATALQ RNTHLVHPGR VQSAVDIKAI ESTLARTVPH YMVPSIYLHI SKLPLNPSGK
LNRRQLREMV GALPRQSLNE YAIKCHSSTT NRPATAQERG LQTIWATVLA LDRDAIGVHD
DFFRMGGDSI AGMQVATKCN AAGMRISSAD LFRHRTIARL VLHLQNTSQE SSAMITLPEE
KFDEWVHLAP IQQLFFENAP DGPNHFNQSL LLRTGRQVDA QELAAGLDIL VQRHSMLRAR
FRRTDSGRWT QQVMSLGPSP SSFYRLFTHG KASPETLPGI FTASQSAIDI QKGPLLSVDL
VDLTDGSQLV YFVAHHLVID LVSWRILHAE LEDYLRTGSL AAMAESTPFL TWCRAQAEYS
AKELSPAQSL PGYQSAANHF DPEGYWGISM ESNTFTQVAS YRFTLDGDTT ETLFGVANDA
LGTQPVEIML AALWYSFTQT LTGRPEPSIY VEGHGREPWT DTIDLSGTVG WFTTMSPLVS
SPWSNLSQAS MRDFADALRY IKDQRRRVPA NGWAYFASRY LNDEGRVVYG RTNPAVEILF
NYMGQYQQLT REDAILQLVG DDIQAGTGAA DIAGDVRRFA LIDVSAFTAH GCLSFDFSFP
ESIQHRDRLQ HWFEQCRQTL IVAASILSLQ TPQKTLTDFP LLPSLTYDQL SQCLDHTLPA
VGLFPSDIVD IYPCSPVQRG MLLAQLRNPQ FYQQRFRFRV LPDTRTEAIG LVGLQQVRDA
WIEVINRHDI LRTIFLPVSD QGYVDQVLLK PGSLHHLVRI GAGEPDTAID PGTPHWVNIS
HDPTGTVVCD WNVSHALVDA VSVAIIQREV SQALQGHLST PPPQQYGNYI QWLSAQNMQE
TQDYWKKYLQ AVEPCLFPRL AAHSDRLTSP VGIQATRATV DREVRIDQLC HQHGITLTNV
FHLVWALVLR TYVGTNNVCF GYATQGRDVP VAGVEEMVGP VVNVLATTLR LQDSESVLDA
LQTHQTHLAD NLAHQNHALV DIYATHGVAG SQLFNTIVSL QDLSHHETAD TQSLRLEVMP
AHDSSEYDIA LNVGVNKTSI ELVCSYQTWS LSAEHADALL RTAARVLDEI LQTPLKTIGE
VDVVSLTCKQ QAMRWNATLP ATVHEYVHEQ IQAQCRLYAN REAVCAWDGH FTFAEIDDLS
SRLAGNLISL GAQPGRIVPI YSPKSRWVVI AILGVLKAGA AFTLLDASHP VARLQEICQG
VNADLIISLA SHASVAAQLA AAIVILDNAP SMSSDEIIMC TRRQSLSTES LAYVIFTSGS
TGKPKGVMVS HSNLCTSAMA QTVALNLTTE SRVLQFASYA FDACILEVIG ALFAGACVCI
PSETDSKDDL VGSIERMRVT WALLTPSVAR ILNQETLPTL ETLVLGGEPI TLSDLEPWRS
RLQLVCAYGP SECTIVSTTT ALSTFPNRSK NIGQRGACAT WVVDPQDYQK LVPFGATGEL
LIEGPIVGQG YLGDAVRTAE CFPPPPRWLS QLRQAPTRVY RTGDLVRYES DGTIRFVGRK
DSQIKFHGQR IELGDIEHHA QDAFRDAQTV IIDLITPGEL HKAYLAAFVL QKDTDAHLDK
VDDDCILLSP SDRFRSRSLA AQEQMHEELP HYMVPAIFLP LSRVPLAKTG KTDRQYLRQC
ALALQGHDLE AYRAASSTKR PPSTGMQQGI QALVATVLGK DTTEVGMDDS FFHLGGDSVQ
AMRLVSVGRQ QGLAVSVLSI FDHPRLADLA EHISSRVKDR NSVRLPSSSL LPSISEAGQL
DRLVEGHPFE KDDVVDILPT TGFQRYWLDM QLSSYVIIDI PGQVDWAQLT KALQRVIENC
PILRTAFVPY RGSTVQVILK TIVSLIEVDL TGDLTSAVEE WCRQDAKTPV SPGTSYMHTV
RASQGATQHK LIMRLSHAQY DAVALSLVLN HLSCTYADQL PLPDAPAFSD YLTYQRTRNK
ERASSDFWGQ LLKGASITNL GPQGSRDDKE ATIARSRHIS VGPLPRGITM ATVVKAAWSL
ILARRTGMCD VLFGQVVHGR NTSFPGIERV VGPCTNITPV RASIAPQWTG LDLLQALQDQ
HRESMAWETV DLDDVLSYCA NWTPGSALQT VVQHQNVVLE DLGLRLGDVP STVSVRAFDH
APREVWLYSS TDDSHPDRLS LRIFSSSWTL DDTIAEELLG LVAEEIVELL RNPEQVLCV