LCSA_PURLI
ID LCSA_PURLI Reviewed; 11872 AA.
AC A0A179H164;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 07-SEP-2016, sequence version 1.
DT 03-AUG-2022, entry version 25.
DE RecName: Full=Nonribosomal peptide synthetase lcsA {ECO:0000303|PubMed:27416025};
DE EC=6.3.2.- {ECO:0000305|PubMed:27416025};
DE AltName: Full=Leucinostatins biosynthesis cluster protein A {ECO:0000303|PubMed:27416025};
GN Name=lcsA {ECO:0000303|PubMed:27416025}; ORFNames=VFPBJ_02539;
OS Purpureocillium lilacinum (Paecilomyces lilacinus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Ophiocordycipitaceae; Purpureocillium.
OX NCBI_TaxID=33203;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], IDENTIFICATION, FUNCTION,
RP INDUCTION, DOMAIN, DISRUPTION PHENOTYPE, AND PATHWAY.
RC STRAIN=PLBJ-1;
RX PubMed=27416025; DOI=10.1371/journal.ppat.1005685;
RA Wang G., Liu Z., Lin R., Li E., Mao Z., Ling J., Yang Y., Yin W.B., Xie B.;
RT "Biosynthesis of antibiotic leucinostatins in bio-control fungus
RT Purpureocillium lilacinum and their inhibition on phytophthora revealed by
RT genome mining.";
RL PLoS Pathog. 12:E1005685-E1005685(2016).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of the lipopeptide antibiotics
CC leucinostatins that show extensive biological activities, including
CC antimalarial, antiviral, antibacterial, antifungal, and antitumor
CC activities, as well as phytotoxic (PubMed:27416025). Leucinostatin A
CC contains nine amino acid residues, including the unusual amino acid 4-
CC methyl-L-proline (MePro), 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid
CC (AHyMeOA), 3-hydroxyleucine (HyLeu), alpha-aminoisobutyric acid (AIB),
CC beta-Ala, a 4-methylhex-2-enoic acid at the N-terminus as well as a
CC N1,N1-dimethylpropane-1,2-diamine (DPD) at the C-terminus (Probable).
CC The biosynthesis of leucinostatins is probably initiated with the
CC assembly of 4-methylhex-2-enoic acid by a reducing PKS. Two reducing
CC polyketide synthases, lcsB and lcsC, have been identified in the
CC cluster and it is not clear which is the one that assembles 4-
CC methylhex-2-enoic acid since both contain KS, AT, DH, cMT, ER, KR and
CC ACP domains (Probable). The polyketide residue might be transferred to
CC the NRPS lcsA, mediated by two additional enzymes, the acyl-CoA ligase
CC lcsD and the thioesterase lcsE. The linear polyketide carboxylic acid,
CC which is released from PKS, is converted to a CoA thioester by lcsD,
CC and then lcsE hydrolyzes the thiol bond and shuttles the polyketide
CC intermediate to lcsA (Probable). The C domain of the first module
CC catalyzed the condensation of 4-methylhex-2-enoic acid and MePro
CC carried by domain A1, followed by successive condensations of nine
CC amino acids to trigger the elongation of the linear peptide. A5 and A6
CC domains of lcsA are proposed to incorporate leucine, A2 AHyMeOA, and A3
CC incorporates HyLeu. A4, A7 and A8 incorporate AIB (Probable). The
CC AHyMeOA in leucinostatin A activated by the A2 might be produced by the
CC second PKS (lcsB or lcsC) present within the cluster (Probable). The
CC MePro is probably produced via leucine cyclization and may originate
CC from a separate pathway, independent of the cluster. Another
CC nonproteinogenic amino acid, beta-Ala, could be produced by an aspartic
CC acid decarboxylase also localized outside of the cluster. Two
CC candidates are VFPBJ_01400 and VFPBJ_10476 (Probable). The final
CC peptide scaffold may be released by the NAD(P)H-dependent thioester
CC reductase (TE) at the C-terminal region of lcsA (Probable).
CC Transamination of the lcsA product by the transaminase lcsP may produce
CC DPD at the C-terminus (Probable). Further hydroxylation steps performed
CC alternatively by the cytochrome P450 monooxygenases lcsI, lcsK and lcsN
CC then yield the non-methylated leucinostatins precursor. It is also
CC possible that leucines can be hydroxylated prior to their incorporation
CC into the peptide (Probable). Varying extents of methylation then lead
CC to the formation of leucinostatins A and B (Probable).
CC {ECO:0000269|PubMed:27416025, ECO:0000305|PubMed:27416025}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27416025}.
CC -!- INDUCTION: Expression is positively regulated by the leucinostatins
CC biosynthesis cluster-specific transcription regulator lcsF.
CC {ECO:0000269|PubMed:27416025}.
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. LcsA has the following
CC architecture: T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-
CC C-A-T-TE. {ECO:0000305|PubMed:27416025}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of leucinostatins A and
CC B. {ECO:0000269|PubMed:27416025}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; LSBH01000002; OAQ83772.1; -; Genomic_DNA.
DR EnsemblFungi; OAQ83772; OAQ83772; VFPBJ_02539.
DR Proteomes; UP000078240; Unassembled WGS sequence.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 11.
DR Gene3D; 3.30.300.30; -; 9.
DR Gene3D; 3.30.559.10; -; 10.
DR Gene3D; 3.40.50.12780; -; 10.
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; IPR013120; Far_NAD-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR010080; Thioester_reductase-like_dom.
DR Pfam; PF00501; AMP-binding; 11.
DR Pfam; PF00668; Condensation; 10.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 11.
DR SMART; SM00823; PKS_PP; 11.
DR SUPFAM; SSF47336; SSF47336; 11.
DR SUPFAM; SSF51735; SSF51735; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 9.
DR TIGRFAMs; TIGR01746; Thioester-redct; 1.
DR PROSITE; PS00455; AMP_BINDING; 4.
DR PROSITE; PS50075; CARRIER; 11.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 8.
PE 2: Evidence at transcript level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Repeat.
FT CHAIN 1..11872
FT /note="Nonribosomal peptide synthetase lcsA"
FT /id="PRO_0000446599"
FT DOMAIN 138..216
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 1250..1327
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 2368..2444
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 3461..3537
FT /note="Carrier 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 4592..4666
FT /note="Carrier 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 5689..5765
FT /note="Carrier 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 6809..6885
FT /note="Carrier 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 7973..8049
FT /note="Carrier 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 9074..9151
FT /note="Carrier 9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 10206..10282
FT /note="Carrier 10"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT DOMAIN 11344..11422
FT /note="Carrier 11"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT REGION 214..234
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 271..681
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 709..1115
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 1366..1783
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 1810..2212
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 2483..2815
FT /note="Condensation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 2915..3316
FT /note="Adenylation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 3583..3998
FT /note="Condensation 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 4044..4447
FT /note="Adenylation 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 4708..5115
FT /note="Condensation 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 5158..5571
FT /note="Adenylation 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 5805..6205
FT /note="Condensation 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 6254..6657
FT /note="Adenylation 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 6932..7385
FT /note="Condensation 7"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 7419..7828
FT /note="Adenylation 7"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 8096..8524
FT /note="Condensation 8"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 8564..8938
FT /note="Adenylation 8"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 9197..9619
FT /note="Condensation 9"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 9663..10068
FT /note="Adenylation 9"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 10324..10620
FT /note="Condensation 10"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 10806..11198
FT /note="Adenylation 10"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 11474..11848
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT MOD_RES 175
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1288
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2405
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3498
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 4627
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 5726
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 6846
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 8010
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 9112
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 10243
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 11381
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 11872 AA; 1294608 MW; E4848B9C59E38C99 CRC64;
MESTNNWATQ AESHLLLDQA VAQAKVLNIT KPNEQEGEAP WAIVISRTNV DNQHEGPEPD
SVLVRRLRKS LVQYMKKLYN SNTRLEQKLN IPKKWIVLDK LPILRVTGLV DVAKLRKLVL
HGEEESTSGS ESDLGKMEMP RTRLDLIVGA MAEVLGRDIS EVDVGKSFVR QGGDSISAIE
LMARCSELDE TLRLRVPDIL LAESLEQLAQ LQPSAEVDAG KATPETKTTT STIQENPFPL
LELSESELFR FKETTAARII ASSSSSDIGL ETAYPCTPVQ EGILLAAIRF PESYRIERIF
EVAKGTMTDS IDLELFEQAW RDVVARHGAL RTVFAPSVRD GAGFDQIVLV GVECDIRRLK
VSPKDGGLAV KLLEQQKAAT FSELRPAHRI TTCSTIEGSV YCKIEIHHSI VDGLSAGLLL
KELRKAYSRR CSGTLAADSE SYHLGRYIAQ IKGHSQKEPL EYWTRTLDGL DPCHFPSLVT
SDAPMTRENR TVQVNVSSSQ AQRFCKTLGI TIPILLQAAW ATVLRGYTQT DDVCFGFLAS
GRDEPVPGLQ NMIGTFIHLL TCRSGAAIIN QYCSLASIQN SLQLGGRSLF NTLLSVVYSS
QDQAGTSDDA VYFKNASTIA SSEYDLTLTA DLTPDTLSLS FTYKTTALSG DNAASLADSF
TQILQTIMSQ PEAQTSNIPT IGPKDLDRVM AAQADLSPAT EACTHWLIAH QVQSQPNGSA
VASWDKNFTY SELNEFSSKL ASRLRRAGVR PDDLVPICFP KCAWAVVAIV AVQQAGAGFV
PLDPTAPPAR LQGILEDTKA TVMLASTECR DAAEQLTGIE TLVFVDEQSV RSLERDEAAL
QDQHPRDAVQ PHHASFAIFT SGSTGKPKGM VISHGSFCTT GVATAPKMEI GPGTRVFQFS
AFTFDVGIFD VLITLMHGGC ICIPDEQQRV SDLAGSIRKL QAEVMYLTPT VAGLLNPDDV
PSVRQLVLMG EAITNKTADK WRGKVVLHGA YGPSEASAAA WNTELGKFGA STANLGRPLA
TIFWVVDPSN IKRLVPVGCI GELLVEGPML ARGYLEGVDK KAAANWLEDV DWLPPVQQSG
WQQPKRRLYR TGDLVRQNGD GTFTFIGRKD TQIKLHGQRV EIGEIEARVH QAMPNTTNAM
VDVVRGDNNE PKYLAVFMWD ALANNNEEVH LAKVVSPERQ RLVSETHEAL ARVLPRYMMP
SSYFILDGTP PRTTSGKVNR RHLVSLVKNI GAEERLRFAP EGQQVVGTDE PTTPLEIELR
TIWAAALGLG NLTIIGRHTD FFALGGDSIG AMKLVNLATR RGLVLNVATV FKAPQLKAMA
AATLSDGKVA VDARPFQLLV DETDIDAMKQ EVAGMCDMES YSDIVDVYPC TTMQIGLMAL
SYKQPTSYTG RIVFSLPSDI DLSRFKQTWR DVMLRNAMLR TRIVDAQTAG MVQVVLRAET
MPWMESDDLD DYLRRDVAIP MTTGKPLSRY AIIRPENGRN LSFVWTAHHA MYDGPSLRLV
AHEVNELYKS GTSGLEEPIP FTRFIQHTQS IADGDAASFW HAQLEGSCRP SFPPAAKNSD
YVRTDGYVTH AMPLPRCANS HITTTTLLRA AWAIVQGKYS RTDDVLYGAV VTGRGISVPG
IESIVGPTVN TVPIRVKLDA SQMVHEYLRK LQEATTEMLA YEQYGLQNIA RLEDGAENVS
SMQTLLVLQA PQEATTLPAG TTELLDLTNA AMHGANFHTH AFILEGIIDE PGKSLTVNVN
FDANMLPEAT VQNICRQLAH VMDMLTRAEG TTALGSIVLA SDAALQAHVT EVNKKRPTWV
SECAHDIISR RALERPSAPA LISMTQTFTY RELDELSTKL AWRLVSLGIE IDSFVPCCFE
KGPLYAVAQI AILKAGAAFV PLEHSHPEQR RAQIVQQLGA KFMLVTPYTV TKMSETTTSI
VGSVIEVTQE FLLSLPLPVG STTTLAGRAS PRTAAYCLFT SGTTGTPKGV IIEHEALSST
CINQGTLLEF GTHTRALQFS SHGFDANMIE TICTLMFGGC VCIPTEHERM NNVPKSIRDM
EVNFAGFTPS FALLIQPDEV PTLKTLIVGG EAITKKCVEQ WWGHVKLFNG YGPTECAVII
SSHRIRSIQD AVDSVLGYNT SSVGWLVEAD GKTLTPPGCV GEIYAQGPSL ARGYLCDADK
TAKAFIEDAS FLVKYDSGKD NTGFAKRAYR TGDLARRMPD GNLQYVGRVN DQQAKLNGQR
LELGEIQHQV KAMASLKSST TSQTAVVVVP QGGSSGSNAA LPRDVLVAFI REARASGDSS
TAVHVLPSSP EFGARVSDLA SDLLTALPQY MIPSLYIPLR NFPLTLSDKV DNKKLVELVS
TMSESDIGTY SLQGHEAAAA LSTERKRAAS SPMELELRDI WATILGRSPD SIMAEDNFLR
LGGDSIAAMR LVSAARRKHI TLTVADIFRD PRLSQHAIMA VRESQDHQEI PAFSLLPADT
TMDSLASALA QQCEDFIDMS QVEDAYPCTA LQEAVMASSV KQKGSYIARN VLRVPPSLDI
NRLCEAWSSV VQTHGILRTR IVQVASSAIQ VVLKESFAWQ DDENIDLETY ISEDSRGLIG
YGTPLMRFAV VGSALGADRT RHLVLTMHHA IYDGWSLPAI LGDVQKAYSG MTVSKGLPYA
AFVNYLSDAN GASSDVYWKS ETDSTKVTDF PRLGSGSRSA KTGQGHNLSA DSSIDFKFPL
IRVKESDITT ATILRAAWAF VLSRYTDSDD VIFGSTLSGR NAALGGIDGM IGPTIATVPV
RVHIDRAQSQ HQFLSNVQQQ GANMIQYEQK GLQNIARISP DAREATRFRT LMVIQTVGNS
ADLLGMTNVT QALNEGFYTH PFILDAAYIS EDEVRTVLHQ FEQVVSQLGS AVELPDHTVD
NINMTSSYDL SRIQTLNSEL PVTQNGLVHD LIASQAKSRG SAEAICAWDG SFTYAQIDDA
STRLAHHLLS LGVGVGPDTF VPFCIEKSAW AIISMVAIMK AGAAFVPLDP SHPVDRRRTV
CQLARARLLL VSPSTSEACQ GIAEQSITVC EALVDKLPES QPLLPSMTKP MNAVYAMFTS
GSTGVPKGVV IEHRSLATAA PAFAKSLYLN SSSRVMQFCS YVFDASLIET LVTLTQGGCV
CVPSDSSRVN DLANAMNEMN VNWTLLTPSV GRLITPKLVP GLKTVVLGGE PVRTDNVETW
HDGGDGPDKA KLILAYGPTE TCIVCSSYTV KDHGDSPMII GQAIGTTFWI ADVNDHDRLT
PWGCVGELLI QGPLLARHYL GDPAKTSASF IEGPVWLPDQ GPGVSRRVYK TGDLVRYNSD
GLLECLGRKD TQVKLRGLRI ELNEVEHQLR TQCAEADQVV ADVVSMSDDP KDSLLVAFIG
LKDTSLLLKD TQVSQALQIH GQSALLSITT DIRTNFVALV EALGQKLPRY MIPTLFMPFK
QIPRVPSGKT DRALLRKVTK ELDEVAFALH SLAVADREKR EPSTPTEREL HLLWADVLGV
AADRIGADDS FLQLGGDSVA AMRLISAARG RGLELSVAMV FDTPQLSLMA ASLDKLAGHG
EQASAGDVGH AEPLSLLNSS IPTAVLLAEA KKACHLDETA TIEDAYPCTP LQEGLMALTE
KQHGAYVMQT VFRLPGTIDL ERFKQAFEVV EASAEALRTR LVSLGEQDFV QVVVSQSQPW
HHGTDIASYL RQDKHEPMSF GDPLCRFALV EDKTSGHTYF VWTMHHAIYD GWSMRLMLEA
FHRAYNSNIT SPQYLIQRQE MVPYSSFIRY TQSLRSDESE SWWASHLDNA AATPFPRTSQ
GRSRSGQGEN WRQSLSFATS GSFKSLGVTK AALVRAAWAL VIARHADSDD VVFGSTVSGR
TAPVQGLEHI IGPAIATVPV RIKIDQTRPI GDFLREVQSQ TNAMIPYEQV GLQNIAKISP
AARDACNFQS LFVVHPPRLT KLQGDDLGDS LLDIQPTSDS LSVDGGQFFT NPLVFQCHLG
DGDEVDVTIT YDTGLLSESE AANMGLQFES VVQQLAGTGT SLKSCLPKVV GDVNPLSAHD
FEQMASWNSS AMPEIVDSCI HTLFERQVAL RPDATAVSAW DGVLTYAELD KAANRVAHHL
TTTHKIEPGT LIPICFEKSV WVMVAMMGIN KAGGAWVTLD PSHPEKRHRA ILAQTQSPVV
LTSSHHLKYI SALHSNAIEL SLDLDQTLLR DGTTGSTAPK TAVTADHPVY VLFTSGSTGV
PKGMIMRHGG VSTAMVAIAK RLGMTPTVRI LQFAAYVFDL CIGETLLPLV SGACICIPSE
DTRKDNLAQF IAEQRINWMF QTPSFARVIS PDDVPNVELL LLAGEPVTKD LLETWVGRVR
LFNGWGPSET CLFSSLKEFT PSEQKPSPLN IGSPIGGRCW IVNASDPMRL APIGCVGEVM
IHGPTITKGY LDDPVKTAAA VITELPSWAP TESVHDKRFF KSGDLAYYNP DGTMEFVSRK
DTQVKIRGFR IELSEIEHHI RTKLPAASEL AVSVFKQPGK AAALAVYFSV SGQTYTVASR
DEDVSGLADK ILLPMTTEIR QLISGIISAL SITLPPYMVP TIFVPMSQMV TVTATKLDRT
TLANLSTVIT GDKLAAYSLQ DIDNGHKVAP ETVTETALQR LWATVLDLDS AAAIGRDDSF
LRLGGDSIAA IRLVTLARKE GILLSVRDIF QDPRLHSVAA KADALSKSSS GAFLSAAIPA
FSLIPSETRD ALLQSATQVM GVNGNIIEDA YPCTPLQEGL MALAQKKTQS YTTRNVLKLP
THFDVPRFQR AWEMTVGKCD TLRTRIVVCR GELLQVVLRE PVTWLAQPEP ATGQTQLEAF
VEREKNEPIT HGRPLSRQGI VRDGNSTFFV WTVHHSVYDG WCLPHIFNML VRFYQDEATD
LLHEEQRLFK KYVQFTLEAS QEDLRDFWKR ELDLGRRRLE HFPSSNRVDS SFTNRHEVMK
QSIPSPSKGV SDVTTSTLLR AAWALVLCQW SQSRDVVFGT VVSGRNAPVA GIDSLLGPTL
ATLPITMHVP ENDNGATIAS FLRQVQAQSN AMIAYEHFGV QNIARLSAAA ANACDFQNLL
VIQPAHQFDN ALGIEVVHTI EDHGGYHVYP LVMECLLHDD ATITLQTTFD PSVISSFHAG
AIVKQFSTVI SQLSQKDDSL PLDTVSLFTT EDFAQIETWA DTSDAGMQVC DTTVAAEFTR
VASTNPAAEA VFSISNINDA STKSSWTYKD LDETSNRLAQ YMTSVANIGP GSKVPLCFEH
TAWYIVAMLA VLKSGAAFVP LDPKHPKERM LDVVEQLGTS VILCSPSTSE TASQLATTVF
TVPTVLEEWQ DSRSTSTDLA QRASPSDLAY ILFTSGSTGK PKGVTVSHRA LCTAMKQHRQ
PLGYDIEGTQ TRALQFASHV FDASISEIIA TLFVGGAVCI PTETQRMDPS LLGDFINTAS
ANWALLTPLV AQLLSPQHAR SLRTLVIGGD ALTGKVAAPW LDAGVRVVNA YGPTEACVLI
SANIVQDART ASSIGRGVGF RTWVVDRDDH TKLAPVGQVG ELLSQGPSLA DGYLNDVDKT
NAAFVLAPAW ALRGNTAHIG GRVYRTGDLV RYINPYGELQ YVGRRDTQVK LNGQRIELGD
IEEHMRACLP ELSHIVVEII GVPVGSDESD ILTTLTPEDR KMMSVAIAHM EQRLPSYMIP
SLYIPLRVLP TTSSAKADRK LLHRHISGRT ALEIREAYSL GSNDLEMREP QTEMERLLQQ
LWAEILRLPS DSIGLDTHFI RAGGDSVTAM RLVGTAQQRG ISLSVVAIFE NPTLQAMAQA
AKVVTEHDLH DVPPFSLLPS ALRDVDMLRQ DASRACSTEP EQVLDVYPAT ALQEGIMSLS
QQGDGAYVAR NIFRLPPTMD VDRLKRACED TYTRHEILRT RIVMLRDQTL QVVIDDELRW
RNDTVLKSYV AHCKAELMGY GAPLSRFGIV STSTKETWFI LTLHHAIYDG WSSKLLIDAV
MSAYEVGPHH QIHGSSAPFN RFIKYLVEDC DESASADFWR DQSAGFEPFT FPQGPRQTPS
ATQWARLRHE LPLSSHTIVD VTTNALLRTA WALTLSAHAD TSDVAFGATI SGRNVPVPRV
EMMVGPTFAT VPVRVSMQGA TSIQKLLSDV QKSSIDMVPH QQFGLLKIRD ICPDAQNLCR
FKTLLVVQSS DQESLRGSDG GDFGQVLNVA ADEHGHDNIF RSYAITLECS MHKDRIIVDA
HYDTNTIAPE MMVMVLNHFR RAFVNLSDGQ VDTAMTIRQS LDLFGGEDKR VIDKWAAQTT
APPKQIDACL HDLFRRQVLS RPDEEAVHAW DMSATYAELD DMSSLLAHHL VSQEGHSAGE
SLIPFCMEKS GLALVVMLAI MKAGCGYVPL DPSHPIDRRA QIVSDTGTSI VFVTPETLRD
FSGAATSEIS ERDVKFIVVS HDFIKKLQRG SPAALPSTDP SSTAYTLFTS GSTGKPKGVV
MSHRAACSAI TAQARAFLMT PSTRAINFAA FVFDASVLEI FGTWIAGGCV AVPSDSIRLN
GLVARFMTES QTDWALFTPT FATTLTPKDV PTLRVLVLGG EAIRKENVET WLSKVELFNA
YGPTEACVAT VHHRIMSPTD TGVIGKSVGC RVWVTKVDEI NTLAPVGCAG ELVIEGPGLA
TGYLHDQVKT DEAFVQPSWL THQGCHARAY RTGDIVRYTA HGDLEYLGRR DSQIKLRGQR
LEAGEIEYQI KVALAAARIS GGPGNNKVTQ AQVAVTVLKD ILAPGVSELI AFICFNPISH
DEGPSQEPLL APMNESLRHT VEKLIKEVAL ELPEYMVPTL FVPVARLPLS TAGKADTRRL
NCSVQELPRD ELLHYSISTI TGGTQAKEPP ETDMEVTLQS LWSSVLGISE QAIGRNDRFL
NVGGDSVSAI RLATAARDAG LDLSVSTIFQ HPQLKDMAHE CTMAQEEGSK VQFTSVEPFS
LLTNVTSMDI VVDLAHRIFR PSIQDPAQIV DAFPCTSLQE GMMALTDKEP GTYVARLPFR
IGKHVDMAQF RAAWETVVAA TPILRTRIVS LANGRAIQVV LDEPASWRVV EDAGAGMDLN
SQLANYLEQD KNDHMRYGTP LSRYAVLTSA ESEERLFVWT VHHAVYDGWS LDLIRGKFMQ
AYNGVNSAQI ARPSVSYANF VAHAETVRER GAEYWRHALK GARPVNFPRH NRTRANNARA
DRTDASLKSQ FEVDAFKSRH VRHGEETIAT KASLMRAAWA LVVSAHADGD GVGGEQDVVF
GTTVSGRNAP VPGIEGIVGP AVTTVPLRVR VDPTVTVATY LKEIQSQSND LIMYEQFGLQ
NIAKLGEDAK QASEFRTLLV VHPPKLATDG SATNNSDEPI LSSHLQDDED DAEKTFFTYP
LVFQCHLPED GGRIDITVTF ASSVVSRRQV EQILGHFKQA VNLLAEASTV VKSPSSTNSD
LTLLSQLDLV GSEDIDQFTL WNQEDEPVIQ SACIHDLVEQ QAHLRPDAPA INAWDGQLTY
RELNQAANRI AHKLYYEHNV RPETLVHVCF EKSVWYFVSI LAINKAGGAW VPLDPSHPTT
RHQQVVRQTK AKLVLTSRRN KSLMDGLIDT VLEVTPELDG QLIADEKSSA PALRSGAGPP
AEVKPQNTVY VLFTSGSTGI PKGFVMEHGA VATSQRAIAK RLKMTPHVKI LQFAAFVFDL
CIGEIIAPLI TGACIYVPSE HDRMNRLPEY IKDMGINWAF LTPAFVRTIL PEQVPSLDLV
LLAGEAVGRD ILDTWFGKVR LINGWGPAET CVFSTLQEWT SLEESSITVG KPVGGYCWIV
DAANPHRRVP AGCVGEIVIQ GPTITREYLA NPTMTDATVI AGDELPSWAP RRTDPHWNRF
YKSGDLGFYN PDGTIEFCAR KDTQVKIRGL RVELGEVEHH VRSSLEDAPQ VVVILLKGEA
GNAASSSAKL VAFFCFSQDS KTAGVDLDSD LATVAEDMLL PVSEDLRARL VSMTGQLSVS
LPRYMVPTLF IPCGYMPFIT STKIDRNKLR DIAAQMSAEK TMAYSFVDSV KRAPETKMET
LLQKIWAEIL NIPTSAIGRD DSFIALGGDS IAAIRLTTIA RDYGVEVTVG NVFNDPRLLK
VAEVAIDLRS EDDSAPAWEH LAPEPWTLLP RDIGQDDIDQ VARAQINLPH AAMPVDAYPC
TALQEGLMAL SVKQPGSYIA RFSYQLRSDV SVAAFKQAWN EVVQACSNLR TRIIRLPQGG
SVQVVLQSGA AWESTAGMTL QAYISSSRAT TMTYGSPLSR YALIEGAENY FVWEIHHAVY
DGWSMNLMMD SLHRNYGQSV GPVDPASPTP SLVPYAGFIQ YTLQLDQDAA AQYWRSQLNR
ATKASFPPQT RRSPESTTHT VVRNIAFSHP KNVGVVRATI VRAAWALVLA AYADNASDIC
FGATVSGRQA PVPGIEKIAG PLIATVPIRV RLDRRQPVAD YLMSIQRQAT DMVNHEQYGL
QRIARLSPGA KAATEFSTLL VIQPRHIVSA DKTSDSDNKV MKLVNSDEDA VDGVSTIDNY
FTYPLVVQGH LSDTDVQLHL IYDSGYLDEA EMTILAGQLE NVVHQLVQFS SGDQTLAEVT
LAGPTDIQKA LQWSSSDLGA TRLDVNGVAT PTFQSHVEHQ GILRPNSPAV QSPDGTLTYG
QLNSLSQALA GHLKRNGLVQ QGDFVPLCLD RTFWIPVAML AIHSVGAAFV LFDLDAQSSD
AKRVFRDVGA RSILCLRNHV PAELTLLGLN VVELSGEILH RGQGNLDAPV NANSVSHVLY
PASEAQLQLR DSLGLTSQDR VANLAATNSE IFVSEIMTTL MSGATLCMPP TSTALANQGL
LQYLNQADIN WAILSSVQAS ALQPSDLPKL RGLVIRSPAS LTSLKNWAKA SDSHRILNAL
STPESGFATL HEVRPEIDGT ALGRPLGLTR CWLVDPVNKQ RLAPIGCVGE LVIQSPTLAK
EYLNSPDETL KAFVPTPLDV SADDQTAQRL PSDHGCFRTG YYAKYRPDGT IILVGQVKLG
NSEHRIMEEA PEGVAEAIVT RGRTGELTAF LALDDNAITE TPSSDSATFF VEMSTLSDSL
GSKLVEFVGD LETVLPGHML PRDFVLVRSS GIPLLASTGS PCRSQLLQAM DSLTDKQLLA
VSVSKTLHSH DHSEALSNLE AQLAEIWAQV LGLAKFEQIG RQDNFFKIGG DSISAIDLVS
KARQQGISLT VAEIFANPRL SEMTSVAAFD NDVEIEPVVS HVSAFSLLSS PEGLEAAKAV
VIAEASKQCK VSSAEIEDAF PCSSLQEGML ALAEKQRGSY MGRFVIRLPQ GMDVERFTSA
MAVMVEQCPN LRTRIIMSAS QGRQIQVILN NPISWEQAPS DNSLAECLAA PVSHAAYGGP
LSTYKMVHDE ASCQTCIIWE IHHSIYDGWT LSHMIQVLHR AYDGQSPASP RAPISFSKYV
EHALLTGDEE IRSFWQSQLS DANTAKFPDT TQASPADVRS DGVMTYSLRV PEEHRSSGIT
TANLLRASWA LVLDRYLNSD NDSTDNVVFG ATVSGRDASI PGILGILGPT IATVPVCVRF
GDRRATTVGD YLVAVQDRTN AIVPYEHIGL HNISRVIGNS DATAFHNLLI IQPRMGPQPG
GSDGEAENQR EIDIVDKTMD DNESYYTYPL VFQCVLGDNG DVAVTATYDS RSISQAQMQV
LCRQFETVVR QLGDHSTATR ALSEVDLFTP EDFQIIQSWN REPDRPFGVD EGGEDSCLHH
GVERWASSEP NRPAVVSTAH GTLSYADLDR MSDQLAQHLR TQFGILPDTR VPVCMEKTPL
AIVTILAIMK AGATFVPLEP SHPVERRRAI VSQVGARLLL ISPALAEECR GMTDTVIEVE
PAMFSASNSA QTLPPVSPQG TAYILYTSGS TGTPKGIVVP HAAACTSVQG SASSEGYNLN
PSSRVLQFSS FVFDVSIAEI FGAFMFGSTL IMPSSSERLS DISAFIQVNN VNTAMFTTSF
AKTLEPDNVS SLSTLVLVGE PPTRESLTKW VGRVDRLVNA YGPSETVMFC GTHVFTSETE
MPSTVGRGVP HVGIICWITE IDNPQRLAPL GCIGEIVVHS GSLASGYLND ESRTNATFFH
GVPWLAPTKK DKRHDSYTWY KTGDLGRYNL ETGMIEYLGR RDTQVKLRGQ RLETAESEHH
VKRLLPDVEH AAVDVLKRDG REMLAAFVGF APHSSHAMGG EEQEPTFAPI TDSLRSAFVA
LTEGLKQVLP IYMVPTLFVP VTRMPFNNSL KLDRRKLQQM VEQVSTQELL SFSVAAGQGS
NGVKTPPATP TECALQAIWA KVLGVDAQII GREDTFNRHG GDSIATIQLV SVANQQGVNL
TAAEVFQHPR LQEMAACIDA KSEVPVSADE DLEPFGLLSG LSARTTVIQE AARQCETPES
SISDAFPCTP LQQGLIALAQ KQPGSYVARF ALHLPTHVDM GRFRLAMERM YQECSNLRTR
IILQDDELIQ VILDEDLPWM EIRSIEPTLE GALESRTDLQ WSAGFGQRLC RFVLVHDGSG
SIHLVWDIHH SIYDGWSIGL MLDIAQKLYN EDNTVTKPVS FSQYVKYVTA ASAESGSMSS
KQYWQSRFAN VNISHFPKAS SDNDMESPDE GAKTDATMKH ELSWSAQHSL PNGVTLPTIL
RSAWALVLSR YIDSNDVVFG NTVTGRNASV PGIVNVVGPT IGTLPIRVRI HDNEHADASV
HQFLQRMQQE SNDMVPFEHV GLQSIAQMGK ELREACDFQN LLVIQPGARR STPEAAFTSD
EMNFFDIEDL TSSPSSNSQR YHVYPLVFQC IIESSVSVRL LATYDTRSLP MATMEAICHH
FSQAATQLVE AASSTHTVPL SSITLTSEYD IEKVLGWTSD PSSTMQPWDS CVHDLVSQQA
RIGSLEKEAI YAWDGTMTYA ELDQVSSQLA VHLRQLGVGP EDFVPICYEK SMWTIVAMLG
IMKAGGAFVP LDPAHPPARR EALVKDIGGV QVILASPSTA TSCAKLDAEV VVLSPALISQ
LPSLSTTEDA FAVNPRSAAY AIFTSGSTGK PKCVIMEHLS LCSSIRGHAA EIGLNAESRV
LQFSNYVFDV SLGEILSTLV FGGTVCVPSD TQRLAGGELP SFIAQSRANV AMLTPSVVST
ISPSEVPTLK TLVLGGEAPT RDNLQTWGGH VRLVNGYGPA EACIYCSAFE IPSSTAYPNV
VGRGSNFKLW VVDVNEPSRL APIGCTGEIL LEGPGLARGY MNNKEATSRA FIELERADWF
DQEPRQAKRR FYKTGDLARY TTEGTVQYLG RKDTQVKLHG QRIELGEIEH QVKTTASSRG
LVEHVVVDIV QKESQAALVA IVSLAAVANG LSASAPVMMM MMTDALRAKF SSLAADVGLV
LPHYMVPQYF ILASHLPATA SGKIDRTTLR GHINELSSSD LRAYYVEPSG DASTHVGNSV
APKAPSSDLE RGLQQLWARV LNLSTDVIGV DDNFYRLGGD SIRVITMAKR VKEEFGVSLG
LGQISGKATT ISKLAIDIEA ARAASDSTLT AVAKPDGNAH IDLQSEIARF TATLTDGTTQ
SPRQSMVSVP TRATVFLTGA TGFLGTEILR QLLLSPAVAR AIALVRSRSK QDGVERIEKT
ATAIGWWSSI DAVEKEKLEV WTGDLSTPRL GLGSDQWGQL VGSVDAIIHN GAVVNWQADF
ETLRAANVSS TADLLSTITA RNSRSKLVYV SGGIKLVDTQ KNQSEVAAEL SRGGTGYMQT
KFLAESLVNN TAAHLAGRTS PSNGQQNRVS IVKPGVILGA GVEGAANVDD YLWRVVASAA
AVNAYPSEPE DHWLYLDDAA SVARSVIDQL RFEAPVPSGV TSFVDLQRGM TVSAFWGLVD
KELAATAGAR HPGGLSSLSW DDWTRVALAQ MESVGESHPL WPVQHFLGRL GTGLSPVKQA
TEQSVSRTDR ELEKVVERNV RYLVRQGLIG DGEGRSNGGA FRRTGLNQKL GE
