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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
 
 
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