MLFA_ASPHC
ID MLFA_ASPHC Reviewed; 5098 AA.
AC A0A395I3F8;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 05-DEC-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 ORFNames=BO97DRAFT_465346;
OS Aspergillus homomorphus (strain CBS 101889).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=1450537;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CBS 101889;
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; KZ824274; RAL14731.1; -; Genomic_DNA.
DR SMR; A0A395I3F8; -.
DR STRING; 1450537.A0A395I3F8; -.
DR Proteomes; UP000248961; 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..5098
FT /note="Malformin synthetase mlfA"
FT /id="PRO_0000446431"
FT DOMAIN 756..829
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1853..1930
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3029..3105
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 4576..4652
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 867..1298
FT /note="Condensation 1"
FT /evidence="ECO:0000255"
FT REGION 1326..1715
FT /note="Adenylation 2"
FT /evidence="ECO:0000255"
FT REGION 1930..1960
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1993..2022
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2063..2478
FT /note="Condensation 2"
FT /evidence="ECO:0000255"
FT REGION 2501..2893
FT /note="Adenylation 3"
FT /evidence="ECO:0000255"
FT REGION 3122..3587
FT /note="Condensation 3"
FT /evidence="ECO:0000255"
FT REGION 3608..4027
FT /note="Condensation 4"
FT /evidence="ECO:0000255"
FT REGION 4052..4442
FT /note="Adenylation 4"
FT /evidence="ECO:0000255"
FT REGION 4689..5016
FT /note="Condensation 5"
FT /evidence="ECO:0000255"
FT COMPBIAS 1931..1954
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1993..2017
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 1890
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3066
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 4613
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 5098 AA; 561352 MW; 34A126C8E29C047F CRC64;
MSRFSCIFPT LTDGYVPNPD NTRAAGQRTY AIDLSRRNAP SSETESHILA AWGLVLYSYV
GTDEVAFYVV PKSGPDTTAL AELKVEGDMS RQALTHAAEQ LFPTGSVGAG QVSGDTANTI
IDFANDIESL FVTQTEESFL SLHVHGDEQG HVSLSLTYHL SLLTDLQAAN VGTAMAQALA
EVGKDDCDRL IKDLNLMSPT HLEHIWKFNA NVPGTWEECF HDVIERHAAN RPHSLAVDAW
DTKLTYADLV REASLLAAYL QQRGVRPGSV VPISFERSGA ALVAMLAVSK AGGAFVSVPP
NLPAGRLDAI LEVIEAPFVV TWSKYESFWA ERLPTLPIDN YPKPSADAAV EALGKPEDLF
YVIFTSGSTG RPKGCMLSHS NWLNGALRNA PSWKYGPESR VLQMLSHTFD MSLLEICTSL
GSGACVCVPR TEEIETSVSD AINRWQVNHV IMTPSLARAL RPDDVPGLKT MCLGGEAFPK
EIVTMWSERI NLWQFYGPSE CSINSSSRAI TRPDADPLNI GPPNSAACWV VDTQDYNKLV
PVGAIGELLV SGPIVGMGYL KNPVKTAEAF LDQVGFVAKD DPQFGGFRFY RTGDLVRWNS
DGTITFCGRA DTQVKLNGQR LELAEVEYQL GLEAGVQYAI AMAPQTGRCK NNLIAILTVK
GTSTSNQGNA AEISLLDRRD PIVQQTVKKL RSQLQHALPR YMVPTIWAFV GRMPMSPSGK
IDRVQLRNWV QDMSQEAFDA ITGRSFEAED HVLGLSRLEQ EIQLAWAEAL GLSAAEVGVQ
QPFVALGGDS IKALDAVARC RARQIKISMV HILSCEGVRE AASLAKVQET PAQQVAEMAV
DYSDLWTRLS TDYELGKLGI SQLEEVEDVF PCTTMQEGMF LGQIRRPGAY HMRFFHRVQL
KGGCLPPVER IQQAWAALVE RHPSLRTVFV DDLSPEAIYH SVVLRSVPME LTMREVPRDL
NPEAALAMFT EELVPFRPNA PLHRMLLLTC RGRVPYFMLE ISHVIMDGYA LSVFRREFIQ
ACSSTAPLPR GPDYRMFANY HRTRQTDESA KYWTDYLADC TGCHIPTHAE AAPTDVPPKW
PRTLQRRDFG FDNSAAFLQR CKERQVTLAC AIRAAWALVL RAYTQSQDVC FGYVSSGRNV
PVPEVETIFG LCLSMQVCRA KLSEASTMAR LARKIQEDYV ASLPFQHYPL AEAQRGLKQT
RGQGLFNTAI SMEWVPPTAE DENALLDLEE IREQDDPTEY DIAISVDVHE GHIKLGFLYW
PNLTDFEIAH LAEALQGALN CFAFQPDEAL DSLTLLQASD FCSTLGDRST MLPLEAVRGN
VMSMIDGWVT RQPESAAIDG WDGSLSYKKL HEQSSWVAHN LLHQGVQPGD RVLVCADRSS
RTVATILGLV RAGCVLVLST PTDPEKRLQW LAQKCNAALV VADPAYEKRF ATAGPRVLST
TSVCVPAAWD YEFPALDEQD LVSILFTSGS TGTPKGTLMD HGALATSVLL GHGRTLRFSR
HTRMLHFASL TFDAALAEIF TTLAHGGCIC VPCEEDRLSD VPGCISRFAV NTAMLTPSVG
RLLDPGALPT LKALVMIGEP MSRLDVERFA PVLDLYNGAG PTETSIMVTI AGPMKPTDDP
VNLGYPVTGV RLWVTEAENP NRLAPLGAVG ELIVEGRLVT RGYLDDPSRT QEAFLTSLPW
LPSQHALYRT GDLVRYADDG SLRYMGRKDT QVKLRGQRIE LQEVEYHLRK ILPQAQVVVE
MVVPEGKMRA QASLVAFVSG LTAADVESSS ACNFEESMPM SQIVFPRSAL QTLEEALPRH
MIPSVYYALD TIPLSINGKV DRRRLREMGA ALLASSAAHK GAVDEMSEPV KWTAASELER
TLSELWAATL ELEAEAIHCD DSFFELGGDS VSAMKLVAMA RDQFKLSLSV PQMFRYPTIR
QLAAEFGEPA GQSASSASST TEEGFTFSTP DDSSTNDGVD DDFLQLATAQ LAQLAREKGK
KVDIASLLKQ LQGSSSSSKT PSGSSSSSSS SSRKKKSARV VSPVKVPAPV PVPFSLLDGG
ADVVEKVCVY AVDQCKIPHE DIEDIYPATA LQEGMMALMA RTPGVYTTTL TCELPEQVDF
ARLHAAWDKT AEAHPILRTR IILTDNNTAM QVVQRAKELP WDTYYLQDGD ILPDLTSNMT
LGSPLLRLAE IHRQDQPRML MVAIHHALYD GWSMPLLKQA VEDVYHGRPL QSQPFTPFIN
YLNAGKPAAQ AFWTAHLDSF AGGVFPTLPS IDHHVQLTER RTRSLTVPAA LPGSQYTLAT
KIQTAWAVTV SRYAEAEDIV FGTVSTGRSA PVPAIDRMVG PTITTVPVRI SLSDQAERVI
SLLQRVQEDG WNRMDHEHLG LQHIRRLGES CAATCSLQTL LVIQPREQPR AKSGSTLLAG
LQDVAELEGV DTYPLMLVCE PDGASLHLTA MFDPAVLDEV MLGRMLAHWE LILTQLWSEP
DMAVMELDAL SHSDRQTLVR WNAGERVADG CAHDAVHEWS VRTPHAPAVC AWDGEWTYEE
LEKCSSLIVR QILAHGVSSG DFVALYHEKS RWAAAGILAV FKAGGILVTL DPAHPKDRIK
DIVYQARPRL ILTSQSLLGE ARELEVPVLS VSFAASQQTP EECSPLPIVS STQAAYAPFT
SGSTGRPKGI VLDHRGLAAS TASVAHACLL RPASRVLHFA SFAFDASMME HLIAWHAGGC
LCIPDETARQ TDLASCIRDF EITWAFLTPS CLRLITPDDV QSLEALGLGG ESMTSEDISI
WGPRLRQIVQ LYGPAECCIV AALTEVTKPS ENRLIGRPNA CRCWVVDPQN PDRLAPLGAV
GELVIEGITV GWGYIDDPER TTQAFIRPPT WLQTLYPNSQ QPGRLYRTGD LVRYAGADGK
LTFIGRRDGQ LKLHGQRIEL ADVEAHLRPL MPGTQKIVVE MVHSADNQHP LLAAFVEEPL
ASQNPSEQEV GLLHPSQTQC ALDVKAIDSV LSRMVPQYMI PSMYLHISRL PLSASGKLNR
RHLREIVAEF PRQRLNEYAA GSGLTVPDRP VTAQEREMQA IWARVLSLDP DTIGINEDFF
RIGGDSISGM QVATKCNAAG MHITGADLFR HRTIEQLMRH LSATRKSGCA SISLPAEPVG
EWVALAPIQQ LFFEIAPQGP NHFNQSLLLR TGRRVSVEEL AGGLDILVER HSMLRARFCR
DDSGQWSQQV RSLGSYPASA FYRLATHNQV APQSLPTLLT ASQLALSIQE GPLLAVDLVD
LADGAQLVYL VAHHLIIDLV SWRILHGELE EYLQTGSLAS ATGSVSFLTW SRAQAEYSAN
HLTPTRALPD FQEANDGFDA PKYWGISSES NTFGQTSSSR FTLDRTVTDQ LFGSANNVLD
TRPVEILQAA LWYSFTRSLT DRPGPSIYVE GHGREPWTES IDLSRTVGWF TTMSPLVSAP
WDSLSRTRMR DFLDALSYIK DQRRRIPANG WAYFTSRYLN DEGKVAYGRM KSVVEIMFNY
MGQYQEMNRE DAILQLAGDD IQSGTGAADI AGNVPRFSLI DVSAFTANGC LTFEFIFPES
MQQDARLKQW FKECERTLIV AASTLSTESP RKTLTDFPLM PALTYDQLNQ CLDQTLPSMG
LCARDVVNIY PCSSVQQGML LAQLRDQQAY QQRLRFQVNS RGPTDRLTLE RVKDAWTEVI
NRHDILRTLL LPVSDYNHLD QVVMAPGSLQ HLVRMNAMDA NPTQGLPHSI NITSDSTGTV
ICEWNVSHAL VDAMSIAVIQ REVNQALQGS LGQHQNLPRY ADYVQWLSLQ DNTETQAYWQ
NYLEGVEPCL FPKLTSLPDK VNPEGTISAI RATWTRDARM HDLCQKHGIT LTNLFHMIWA
LVLGAYVGTD EVCFGYTTLG RDVPVDGVEK MVGPLVNVVA TIVQLQEDDS ILNALLTHQT
HLTNSLQHQH YALADLYASS GLVGSRLFNT IVSLQDMSHF DAPDEQPTWL EMLPANDVSE
YDVALNIGVD QSSIQLVCSY RTLSLSAVQA DALLRTASHV LSEMLRDPTQ RFSELEVISP
ECKEQLMKWN AAMPAPTEEY IHEKIQGQCR LHASREAVCA WDGIFTYAEV DDLSSRLAAR
LIRMGVTSEH IIPIYAPKSR WTVIAILGVL KSGAAFTLLE TSHPMARLQV ICHEIKADMI
IAPASHAGPA ANLAPIIVGL DRITSMSPQT SDLLPTVGMP PAAEALAYLI FTSGSTGNPK
GVMVTHQNLC SNASIMTTSV NMMSDSRVLQ FASHAFDGCL WEILGPLFAG ACLIIPSESE
SQEDLAGCIE RMVVTWAFLT PSVARILKPE TLPSLRVLTL GGEPIAASDL DMWRGHVQVV
CAYGPTETTI LASTTSPSTF PTDGRDIGVP TGSSLWIVDK RNYLKLAPLG ATGELLIEGP
NVSQGYLGDP EKTNEAFPVA PRWLSQLRQS PTRIYRTGDL VRFDTSTGTI RFVGRKDNQI
KFHGQRIELG EIEHHAQQAF SNSSTVIVDL ITPAQPQRPY IVAFVHQPDT KTATADPIDA
ILLPPSESFR AEALGAQNHM HKRLPHYMVP TVFLPLQWLP LSGTGKADRK RLRQCALALP
SPDLDAYRAT ALMKRMPSTA AERKMQELVA TVLGRGVSEI GMDDSFFYLG GDSVQAMRLV
AEGRHQGLAL SLRAIFDAPR LGDLAYRTTN LVKVNQPIQA TSPVTLRDEC NHIETIVATH
PIKKTDVVDV LPTTSFQRHW LDIQLMSYIV VDIPGPIDPE RLLTAMQRVV EAHPILRASF
VPYEDTTMQV ILRTRVAMTA ADLSTTTVED ICRQDEDAPM ILGTPYMRVI LASQGDVGHK
LIMRLSHAQY DAVSLSLLMN DLRHAYANET RPFPSSHSPP FTDYITYQQT LRADPTATTF
WHSLLQDVPI TCLNLQPAET STSNGTPITR TRDINISPFP SLPNGITIAT AVKAAWSLVL
AQKTDSLAVI FGQVVHGRGI ALPGVEGIVG PCANITPVVA RLGRQTAGLE LMQTLQDQHR
SAMPYETVDL DDALAYSKDS QARRKGLQTI VQHQNNVVVD DMELSLGEVK CGVDVRAVDH
VPREVWIYSS VDEKRPRILE VKIMSSTLVL NEEVAEELMD LLIEKIVGLF RDPEGVCV
