ID   MLFA_ASPNB              Reviewed;        4960 AA.
AC   A0A318Z3U0;
DT   10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT   10-OCT-2018, sequence version 1.
DT   23-FEB-2022, entry version 12.
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=BO87DRAFT_442288;
OS   Aspergillus neoniger (strain CBS 115656).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX   NCBI_TaxID=1448310;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=CBS 115656;
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; KZ821472; PYH31622.1; -; Genomic_DNA.
DR   SMR; A0A318Z3U0; -.
DR   Proteomes; UP000247647; 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; -; 4.
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   Pfam; PF00501; AMP-binding; 5.
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; 2.
DR   PROSITE; PS00455; AMP_BINDING; 3.
DR   PROSITE; PS50075; CARRIER; 4.
PE   1: Evidence at protein level;
KW   Ligase; Phosphopantetheine; Phosphoprotein; Repeat.
FT   CHAIN           1..4960
FT                   /note="Malformin synthetase mlfA"
FT                   /id="PRO_0000446436"
FT   DOMAIN          705..778
FT                   /note="Carrier 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   DOMAIN          1777..1854
FT                   /note="Carrier 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   DOMAIN          2955..3031
FT                   /note="Carrier 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   DOMAIN          4438..4514
FT                   /note="Carrier 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          194..564
FT                   /note="Adenylation 1"
FT                   /evidence="ECO:0000255"
FT   REGION          816..1247
FT                   /note="Condensation 1"
FT                   /evidence="ECO:0000255"
FT   REGION          1275..1650
FT                   /note="Adenylation 2"
FT                   /evidence="ECO:0000255"
FT   REGION          1855..1883
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1917..1943
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1989..2404
FT                   /note="Condensation 2"
FT                   /evidence="ECO:0000255"
FT   REGION          2427..2819
FT                   /note="Adenylation 3"
FT                   /evidence="ECO:0000255"
FT   REGION          3049..3464
FT                   /note="Condensation 3"
FT                   /evidence="ECO:0000255"
FT   REGION          3520..3889
FT                   /note="Condensation 4"
FT                   /evidence="ECO:0000255"
FT   REGION          3914..4304
FT                   /note="Adenylation 4"
FT                   /evidence="ECO:0000255"
FT   REGION          4551..4878
FT                   /note="Condensation 5"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        1855..1878
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1917..1939
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         739
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         2992
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         4475
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   4960 AA;  545550 MW;  B0AFDAB945DD9419 CRC64;
     MSRFSCIFPT LTDGYVSNPD HTRAAGRRTY TIDLSGWKAP GSETEAHILA AWGLVLSSYV
     GTDEVAFYVV PTTGPDTTAL ADLKVEGDMS RQSLTYAAEQ LLHPGLVGAG QVSGETANTI
     ITFAKDIESL FVTQTEAANV GTAMAQALAE VGTCDNDRLI KDLNLMSPAH LEHIWRFNAN
     VPGIWEESFH DVIERHATNR PHSPAVDAWD TKLTYADLVR EARLLAAYLQ QRGVGPGSVV
     PISFERSGAA LVAMLAVSKA GGAFVSVPPN LPAGRLDAIL DVIEAPFVVT WTRYESFWAE
     RLPTLPIDNY PKPAADTTVE ALGKPEDLFY VIFTSGSTGR PKGCMLSHSN WLNGALRNAP
     SWKYGPESRV LQMLSHTFDM SLLEICTSLG SGACVNHVIM TPSLARALRP DDVPELKTMC
     LGGEAFPKEI VTMWSERINL WQFYGPSECS INSSSRPITR PDADPLNIGP PNSAACWVAD
     VHNYNKLVPV GAIGELLVSG PIVGMGYMKN PVKTAEAFLE EVGFVAKDDP QFGGFRFYRT
     GDLVRWNSDG TITFCGRADT QVKLNGQRLE LAEVEYQLGL ESGVQYAIAM APQAGLCKNN
     LIAILTVKGT STGNQDTAAD EIPLLDRRDP IVQETVKKLR SQLQHALPRY MVPTIWAFVG
     RMPMSASGKI DRVQLRDWVQ KMNQETFDAI TGRSLEAEDH VLGLSRLEQE VQLAWAEALS
     LSAAEVGLQQ PFVALGGDSI KALDAVARCR ARQIKISMVH TLSCEGVREA ASLAEVQETP
     AQQVAEMAVD YSNLWTRLSD DYDLDKLGVT QLEEVEDVFP CTTMQEGMFL GQIRRPGAYH
     MRFFHRVQLK GGCLPTVERI QQAWASLVER HPSLRTVFVD DLSPEAIYHS IVLRSVPMEL
     RMREVPRDLR AEAALAMFTE ELVPFRANAP LHRMLLLTCR GRVPYFMLEI SHVIMDGYAL
     SVFRREFIRA CSSSAPLPRG PDYRMFANYH RTRQTDDSAR YWTNYLADCV PCHIPTHAVS
     APSDAPPEWP RTLQRRDFGF ENSAAFLQRC KERQVTLACA IRAAWALVLR AYTQSEDVCF
     GYVSSGRNVP VPEVETIFGL CLSMQVCRAR LSEASTIASL ARKIQEDYAA SLPFQHYPLA
     EAQRGLKQTH GQGLFNTAIS MEWVPPSVED EDALLDLEEI CEQDDPTEYD IAISVDVHEG
     HIKLGFLYWP NLTDFEITHL AEALRGAMNR FAFQPDEALN TLSLLQASDV CSALADGPTL
     LPLEAVRGNV VSMIDRWVTR QPEGAAIDGW DGSLSYKELH EQSSWVARNL LHQGVQLGDR
     VLVSCEPDAC WCSRTRRTQR SASNGWQKKC NAALIVADPT YEERFATAGA RVLSTTTVCA
     PAAWDYEFPS LDEHDLVSIL FTSGSTGTPK GILMEHGALA TSVLLGHGRT LRFSRYTRML
     HFASLTFDAA LAEMFTTLAH GGCICVPCED DRLSDVSGCI SRFAVNTAML TPSVGRLLDP
     GALLTLKTLI MVGEPMSRLD VERFAPVLDL YNGAGPTETS IMVTIAGPME PTDEPVNLGY
     AVAGVRLWVT EAENPNRLAP LGAVGELIVE GRLVTRGYLD GPARTQEAFL PSLPWLPSQH
     ALYRTGDLVR YADDGSLRYM GRKDTQVKLR GQRIELQEVE YHLRKSLQQA QIVVEMVVPA
     GKMRAQASLV AFVSGLTAED VESSSACNLE GTILISQIVL PKSAFQALEE VLPRHMIPSV
     YNALDTIPLS VNGKADRRRL LPPIRTPLKE SKSVKWTPAS ELERTLLELW AATLGLEAET
     IHGDDSFFEL GGDFVSAMKL VATARDKFKL SLSVPQMFRY PTICHLAAEV GEPAGQSASS
     ASSTTEEGFT FSTPDDSSTN DGVDDDFLEL VTAQLAQLAQ EKGKKVDIAA LLKQLQGGSS
     SNKTPSVSSS SSSSSSSKRK KNAAKAESLA EAAAPIPVQF SLLDGGADAL DKVRAQAVEH
     CKITHEDIED IYPATALQEG MMALTARTPG VYTTSLTGNL SELVDLAWLQ YAWGKAAEAH
     PILRTRIILT DNNTAVQVVQ RAKGLPWDTY SLREDDVLPD LTSNMTSGSP LLRLALVHRQ
     NQPRMLLVAI HHALYDGWSM PLLKQAVEDA YHGRDLRSQP FTPFIKHLIA GKPAAQDFWT
     THLDSFVGGI FPKLPSIYHQ IQPTKRRTRP MTLPTAAPKA QYTMATKIQA AWAVTVPRYA
     EVNDIVFGTV STGRSAPVPA IDRMVGPTIT TVPVRISLGD QADRVLSLLQ RVQEDSWNKL
     DHEHLGLQHI RHLGESAAAA CSFQTLLVIL PREQPDTKYR STLLSGLQDV AELEGVDTYP
     LMLVCEPDSA RLHLTAVFDR AVLDGATLDR MLAHWELVLT QMWNEPDMAV IEIDAVSCSD
     KETLMRWNTG ETIPDGCAHD AVCEWSRRTP HAPAVCAWDG DWTYEELERC SSLVASQIFA
     HGLSSGDFVA LYHEKSRWTA AGILALFKAG AILITLDPAH PTDRIKDILD QARPRLILTS
     QSLLDVARNL ETPVLSVQLA ASQPLPEGWS SLPTISPTLA AYAPFTSGST GRPKGIPLDH
     RGLAASTASI ARSCLLRPAS RVLHFASFAF DASMMEQLIA WHAGGCLCIP DETARQTDLA
     KCIRDFNVTW AFLAPSCLRL ITPDDVPSLQ ALGLGGESMT SEDITIWSPR LRQIIQLYGP
     AECCIVAALT EVTKPSENRL IGRPNACRCW VVDPQNPDRL APIGAVGELL IEGITVGRGY
     INDPDRTTPA FIRPPKWLQT LYPDDQEPKR LYRTGDLVRY AGVDGKLAFI GRRDGQLKLH
     GQRTELADVE AHLRSLIPGM QKMVVEMVHS ADNQSPFLAA FLEEISTSQK PKEREIGLLH
     LSQSQCALDV KAIDSALSRT VPQYMIPSMY LHISRLPLSA SGKLDRRHLR EMVAELPHQR
     INEYAAGSGL SVPDRPVTSQ EREMQAIWAR VLSLDPNTIG VNDDFFRIGG DSISGMQVST
     KCNAAGIHIT SADLFRHRTI EQLICHINTI RTTDCASVSL PTEPVDEWVA LAPIQQLFFE
     VAPEGPNHFN QSLLLRTSRR VGVEELAGGL DILIGRYSML RARFCRKDSG QWFQQVKSLD
     SEPVSAFYRL AAHNQITRES LPTLFTAAQM ALSIEDGPLL TVDLVELKDG SQLVYLAAHH
     LIIDLVSWRI LHGDLEEYLQ TGSLSSATGS VPFLTWTQLQ AEYSAEHLTP ARALPGFQEA
     NDDFDVMRYW GISSESNTFG QTSTSRFTLD RTVTDILFGS ANKVMDTRPV EILQAALWYS
     CNQALTDHPG PRIYVEGHGR EPWTDSIDVS GTVGWFTIMS PLVSTPWHHL SRKSMRDFVD
     VLSYIKDQRR RIPANGWAYF TSHYLNDEGR VAYGRTKPVM EVLFNYMGQY QEMKREDAML
     QLAGDDVQSG TGASDIADNV PRFSLIDVTA FTANGCLTFE FTFPQLIQQD ARLEHCIKES
     FDGPTCPRRL EYLPLLSRAT GHVVGAAARS AGISATIQVS GYVSRANRPT FIGKVSDHSH
     FDQVVMVPGS LQHLVRGDAM DANPTEGLPH TINITSDSTG AIICEWNVSH ALVDAMSIAV
     IQREVNQALE GSLGQHQNLP QYVEYIEWLT LQDNTEAQAY WQKYLDGVEP CLFPKLTSSP
     DKVNPEATIA AIRATWSRDA RMDELCHKHA ITLTNLFHIV WAIVLGAYVG TDEVCFGYTA
     LGRDVPVHRV ETMVGPLVNV LATTVRHEEN ETILNALLTH QAHLTNSLQH QHYALADVYA
     ALGLVGSQLF NAIVSLQDTS HFDAPDEQRT RLEMLPANDV SEYDVALNIG VDKSSIQLVR
     SYQTVSLSAE QADALLRTAF HVLDEILRDP TQRFCELEVI SPKCKEQLVK WNAGMLAPTD
     EYIHEKIQGQ CRIHNSRQAV CAWDGIFTYA EVDDLSSRLA ARLIRMGVTS EDIIPIYSPK
     SRWTVIAILG VLKAGAAFTL LETSHPMARL HVICNQIKAP MIIAPASHAI PAANLAPILV
     VLDKIMSLAQ ERPVPLPAVG IPPAREALAY LIFTSGSTGN PKVVMVTHQN LCSNASIITT
     SVNMTSDSRV LQFASHAFDA CILGLLGALI AGACLIIPSE SENKEDLAGC MERMDVTWAL
     LTPSVARILK PETLPRLLNL VLGGEPIAAS DLDMWRGHVQ VVCAYGPTET TIVASTTSPS
     TFPMDGKNIG VPSGSSLWVV SRQNYQKLAP LGATGELLIE GPNVSLGYLG DPGKANKAFP
     DSPIWLSQLR KSPTRVYRTG DLVRFDTTTG TIRFVGRKDN QIKFHGQRIE LGEIEHHAQL
     AFSSASMVIV DLITPEQPQQ PYIVAFVHQS DAANETTDTN DTLLLPPSEA FRADALAAQN
     KMYERLPHYM VPAVFLPLHR LPLSVTGKAD RKRLRQCALA LSSPELSAYR ATASRKRMPS
     TAAERKMQGL VATVLGRDPT EIGMDDSFFY LGGDSVQAMR LVAEGRQQGL TLSLRAIFDS
     PCLGDLSDQA KSLIEDNQRA STASRGNLRY DCDQIDKIVA TKSLNKTDVV DVLPTTSFQH
     HWLDAQLKSY IVADISGPID PARLLRAMHR VVEAHPILRV SFVPYENTTM QVILNKAVAI
     KSADPSNTTV EEICRQDADT PTVPGMPYLR VILATQVEAD HTLILRLSHA QYDAVSLSLL
     MNDLGHAYAN ETHPLPSSHF PRFNDYTTYQ QAQRADPTAI TFWRHLLQDV SLTYLNLQPA
     ESSASNGTPI TLSRDIDIAI FPSLPSDITI ATTVKAAWSL VLAQKTNSPA VIFGQVVHGR
     AIALPGVEGI IGPCANITPV VARLGLQTTG LELMQTLQDQ HRSAMPYETV DLDDALAYAK
     DSQAGRKGLQ TIVQHQNNVM VDDMELSLGE VKCGVDVRAV DHLPKEVWVY SSVDEKRPGM
     LEVKIMSSTL VLGEEVAEEL MGLLVEKIVG LLRHPESVCF