GLOA_GLAL2
ID GLOA_GLAL2 Reviewed; 7192 AA.
AC S3DQP3;
DT 20-JUN-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2013, sequence version 1.
DT 23-FEB-2022, entry version 41.
DE RecName: Full=Nonribosomal peptide synthetase gloA {ECO:0000303|PubMed:25270390};
DE EC=6.3.2.- {ECO:0000305|PubMed:25270390};
DE AltName: Full=Pneumocandin biosynthesis cluster protein A {ECO:0000303|PubMed:25270390};
GN Name=gloA {ECO:0000303|PubMed:25270390};
GN Synonyms=GLNRPS4 {ECO:0000303|PubMed:23688303}; ORFNames=GLAREA_10035;
OS Glarea lozoyensis (strain ATCC 20868 / MF5171).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Leotiomycetes;
OC Helotiales; Helotiaceae; Glarea.
OX NCBI_TaxID=1116229;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], IDENTIFICATION, FUNCTION,
RP DISRUPTION PHENOTYPE, AND PATHWAY.
RC STRAIN=ATCC 20868 / MF5171;
RX PubMed=23688303; DOI=10.1186/1471-2164-14-339;
RA Chen L., Yue Q., Zhang X., Xiang M., Wang C., Li S., Che Y.,
RA Ortiz-Lopez F.J., Bills G.F., Liu X., An Z.;
RT "Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in
RT the fungus Glarea lozoyensis.";
RL BMC Genomics 14:339-339(2013).
RN [2]
RP FUNCTION.
RX PubMed=25270390; DOI=10.1002/cbic.201402175;
RA Houwaart S., Youssar L., Huettel W.;
RT "Pneumocandin biosynthesis: involvement of a trans-selective proline
RT hydroxylase.";
RL ChemBioChem 15:2365-2369(2014).
RN [3]
RP FUNCTION, DOMAIN, PATHWAY, AND BIOTECHNOLOGY.
RX PubMed=25879325; DOI=10.1021/acschembio.5b00013;
RA Li Y., Chen L., Yue Q., Liu X., An Z., Bills G.F.;
RT "Genetic manipulation of the pneumocandin biosynthetic pathway for
RT generation of analogues and evaluation of their antifungal activity.";
RL ACS Chem. Biol. 10:1702-1710(2015).
RN [4]
RP FUNCTION, AND BIOTECHNOLOGY.
RX PubMed=25527531; DOI=10.1128/aem.03256-14;
RA Chen L., Yue Q., Li Y., Niu X., Xiang M., Wang W., Bills G.F., Liu X.,
RA An Z.;
RT "Engineering of Glarea lozoyensis for exclusive production of the
RT pneumocandin B0 precursor of the antifungal drug caspofungin acetate.";
RL Appl. Environ. Microbiol. 81:1550-1558(2015).
RN [5]
RP FUNCTION, AND BIOTECHNOLOGY.
RX PubMed=27494047; DOI=10.1021/acschembio.6b00604;
RA Chen L., Li Y., Yue Q., Loksztejn A., Yokoyama K., Felix E.A., Liu X.,
RA Zhang N., An Z., Bills G.F.;
RT "Engineering of new pneumocandin side-chain analogues from Glarea
RT lozoyensis by mutasynthesis and evaluation of their antifungal activity.";
RL ACS Chem. Biol. 11:2724-2733(2016).
RN [6]
RP FUNCTION.
RX PubMed=29352089; DOI=10.1128/aem.02370-17;
RA Mattay J., Houwaart S., Huettel W.;
RT "Cryptic production of trans-3-hydroxyproline in echinocandin B
RT biosynthesis.";
RL Appl. Environ. Microbiol. 0:0-0(2018).
RN [7]
RP REVIEW, AND DOMAIN.
RX PubMed=27705900; DOI=10.1515/znc-2016-0156;
RA Huettel W.;
RT "Structural diversity in echinocandin biosynthesis: the impact of oxidation
RT steps and approaches toward an evolutionary explanation.";
RL Z. Naturforsch. C 72:1-20(2017).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of pneumocandins, lipohexapeptides of
CC the echinocandin family that prevent fungal cell wall formation by non-
CC competitive inhibition of beta-1,3-glucan synthase (PubMed:23688303,
CC PubMed:25879325, PubMed:27705900). The 10,12-dimethylmyristoyl side
CC chain is synthesized by the reducing polyketide synthase gloL/GLPKS4
CC (PubMed:27494047). The thioesterase gloN/GLHYD exclusively interacts
CC with gloL/GLPKS4 to maintain turnover of the polyketide side chain
CC (PubMed:27494047). The 10R,12S-dimethylmyristic acid is then
CC transferred to the first thiolation domain of the nonribosomal peptide
CC synthetase gloA/GLNRPS4 by the acyl-AMP ligase gloD/GLligase, followed
CC by its acylation to L-ornithine to trigger elongation of the cyclic
CC hexapeptide (PubMed:27494047). L-ornithine, 4R-hydroxyl-L-proline
CC (generated from L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-
CC L-homotyrosine (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC,
CC gloJ/GLHtyD and hydroxylated at C-3 by the dioxygenase gloM/GLOXY1),
CC 3R-hydroxyl-L-glutamine (generated from L-glutamine probably by the
CC dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-
CC proline by the dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or
CC 3S-hydroxyl-4S-methyl-L-proline (generated from L-leucine by the
CC dioxygenase gloC/GLOXY4 to yield pneumocandin A0) are sequentially
CC added to the growing chain (PubMed:25270390, PubMed:25879325,
CC PubMed:25527531). The last C domain of gloA/GLNRPS4 is proposed to be
CC responsible for cyclization by condensation to form the peptide bond
CC between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline (for
CC pneumocandin A0) or 3S-hydroxyl-L-proline (for pneumocandin B0).
CC Finally, the subsequent C-4 hydroxylation of 3S-hydroxyl-L-homotyrosine
CC and L-ornithine dihydroxylation at C-4 and C-5 are performed by the
CC cytochrome P450 monooxygenases gloP/GLP450-1 and gloO/GLP450-2,
CC respectively (PubMed:25879325). {ECO:0000269|PubMed:23688303,
CC ECO:0000269|PubMed:25270390, ECO:0000269|PubMed:25527531,
CC ECO:0000269|PubMed:25879325, ECO:0000269|PubMed:27494047,
CC ECO:0000269|PubMed:29352089, ECO:0000303|PubMed:27705900}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:23688303,
CC ECO:0000305|PubMed:25879325}.
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 (By similarity). Each module is responsible for the recognition
CC (via the A domain) and incorporation of a single amino acid into the
CC growing peptide product (By similarity). Thus, an NRP synthetase is
CC generally composed of one or more modules and can terminate in a
CC thioesterase domain (TE) that releases the newly synthesized peptide
CC from the enzyme (By similarity). Occasionally, epimerase (E) domains
CC (responsible for L- to D-amino acid conversion) are present within the
CC NRP synthetase (By similarity). GloA has the following architecture: T-
CC C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C (PubMed:25879325,
CC PubMed:27705900). {ECO:0000250|UniProtKB:Q4WAZ9,
CC ECO:0000305|PubMed:25879325, ECO:0000305|PubMed:27705900}.
CC -!- DISRUPTION PHENOTYPE: Blocks the production of the two major
CC pneumocandins, A0 and B0 (PubMed:23688303).
CC {ECO:0000269|PubMed:23688303}.
CC -!- BIOTECHNOLOGY: Pneumocandin B0 is the starting molecule for the first
CC semisynthetic echinocandin antifungal drug, caspofungin acetate
CC (PubMed:25527531). Pneumocandin B0 is a minor fermentation product, and
CC its industrial production was achieved by a combination of extensive
CC mutation and medium optimization (PubMed:25527531). Inactivation of
CC three of gloP/GLP450-1, gloO/GLP450-2, and gloM/GLOXY1 generates 13
CC different pneumocandin analogs that lack one, two, three, or four
CC hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-
CC homotyrosine of the parent hexapeptide (PubMed:25879325). All of these
CC cyclic lipopeptides show potent antifungal activities, and two new
CC metabolites pneumocandins F and G are more potent in vitro against
CC Candida species and Aspergillus fumigatus than the principal
CC fermentation products, pneumocandins A0 and B0 (PubMed:25879325).
CC Moreover, feeding alternative side chain precursors yields acrophiarin
CC and 4 additional pneumocandin congeners with straight C14, C15, and C16
CC side chains. One of those compounds, pneumocandin I, has elevated
CC antifungal activity and similar hemolytic activity compared to
CC pneumocandin B0, the starting molecule for caspofungin, demonstrating
CC the potential for using gloD/GLligase for future engineering of new
CC echinocandin analogs (PubMed:27494047). {ECO:0000269|PubMed:25527531,
CC ECO:0000269|PubMed:25879325, ECO:0000269|PubMed:27494047}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; KE145356; EPE34341.1; -; Genomic_DNA.
DR RefSeq; XP_008078276.1; XM_008080085.1.
DR SMR; S3DQP3; -.
DR STRING; 1116229.S3DQP3; -.
DR EnsemblFungi; EPE34341; EPE34341; GLAREA_10035.
DR GeneID; 19469082; -.
DR KEGG; glz:GLAREA_10035; -.
DR eggNOG; KOG1176; Eukaryota.
DR eggNOG; KOG1178; Eukaryota.
DR HOGENOM; CLU_000022_60_0_1; -.
DR OrthoDB; 4243at2759; -.
DR Proteomes; UP000016922; 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; -; 7.
DR Gene3D; 3.30.300.30; -; 6.
DR Gene3D; 3.30.559.10; -; 7.
DR Gene3D; 3.40.50.12780; -; 6.
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; 6.
DR Pfam; PF00668; Condensation; 7.
DR Pfam; PF00550; PP-binding; 7.
DR SMART; SM00823; PKS_PP; 7.
DR SUPFAM; SSF47336; SSF47336; 7.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 5.
DR PROSITE; PS00455; AMP_BINDING; 6.
DR PROSITE; PS50075; CARRIER; 7.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat.
FT CHAIN 1..7192
FT /note="Nonribosomal peptide synthetase gloA"
FT /id="PRO_0000444480"
FT DOMAIN 105..181
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 1190..1266
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 2288..2364
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 3378..3455
FT /note="Carrier 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 4453..4529
FT /note="Carrier 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 5551..5627
FT /note="Carrier 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT DOMAIN 6645..6721
FT /note="Carrier 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:25879325"
FT REGION 1..52
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 239..634
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 675..1047
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 1316..1736
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 1758..2154
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 2407..2829
FT /note="Condensation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 2849..3245
FT /note="Adenylation 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 3502..3891
FT /note="Condensation 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 3920..4320
FT /note="Adenylation 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 4574..4971
FT /note="Condensation 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 5013..5414
FT /note="Adenylation 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 5674..6071
FT /note="Condensation 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 6111..6507
FT /note="Adenylation 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT REGION 6795..7178
FT /note="Condensation 7"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25879325"
FT MOD_RES 142
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1227
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2325
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3415
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 4490
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 5588
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 6682
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 7192 AA; 796110 MW; DC55AF2A592E6DA1 CRC64;
MTPSRSLENG EKQMNWNESP QTASPKNVLR DSNSNGNYVN GHGTNINGDG SDGVGNGINA
NGSATKINGN GTYTNGNGAH TNGNGVHTNG HGISLESQTS DSKVHSTSKF KEEFRAICAK
VLKIDIEELD DTCSFVSLGG DSISAIKLVT ECEVRGIELK TVDVISTHTI SGLFATANFR
PFGKHSNGKT GISYSRNQED DDPSPFALWT AHRDSDLIEK RQRLEEIAVL CGVETEEIED
VYPCTPLQEG LIAITTRQPT AYVQRRVCRL TNEIDLERFW AAWETLVANV ASLRTRIIMG
PGGQSLQVVI REKLLWRRGS NLGRYLSRDR ADGMMLGQPL ARFGRIQEET GSFFVWTAHH
SIFDGWSALL LYRQLLAIYQ QSYVPRLVPF SRFLRYLAEQ DSTAATRYWH SQLHGDTMAD
WPALPSSNYQ PQPQHVFRSS INLPHGYKPG TIMISNLLRA AWALVMAQYS GNDDVIFAVT
VSGRSAPVSQ IADIIAPTIT TVPVRIRIDR SMSIAELLLE IQSQAAKMIE HEHTGLQTIK
KLLPEFGTAL ELRNLLIVQP EAESDDYVYK EFPGLEAIRE AMEDFDNYGL NVECILGSQS
IEVLVNYDDH VINTMHLRDV MGQFTYTVQC LCNPSVSKLS VNDVATIKTS DQQRILEWNE
HIPPSVDRCI HHLVQDQVNI QPAKLAVDAW DGKYTYADLA RESISLAHHL VGLGLGPEQP
VGLCGSVLPL GVSHPFARTS GIVQEAKVRI VLVDESQRTE LAKLATTLIV VDSELIAALP
SEAKPPETGV TPENVAWILF TSGSTGTPKG VVLQHASLCT SLIGHANTVG INKYTRTFQF
AAFTFDVSLC DIFSTLQAGG CVCMPSEDER MNSLAEAASR MEVNYAELTS TVTETISPSQ
VPSLATLALS GEALKPSVLS TWARHSSVFN SYGPTECSIV ASNSKRLSNV EEAQNIGGPM
SSIFWVVQAA NFHQLCPIGA PGELLIEGPL LARGYLNDEV KTEKAFIIDP DFTKQLGLSP
GRRMYRTGDL VRQNQDGSLM YLGRCDSTQV KVRGQRVEVS EIEYQISRQL PEIQTVAVEM
LQRGTQASLV AVVNFAMDSK YAAPAAFDTT TTKTETIFST DALRAVFQDL QLALSQVLPA
YMIPTLYAPM STIPMNASGK LDRRVLRTKL DSMSFDELRV YMADDGPKAA PSTDAEKQVQ
SLWSEVLAIN PQDIALSDNF FRIGGDSIAA MRMVALKASR RLRLTVADVF QHPQLSDLAF
VIQRRLQMVE DGVQEEDSAP FDLWAKFKVD GLDSTKRAQE LAIIATRCDI RVDDIEDIYP
CTPLQEGLIA ITTHQPTAYV SRQIYKLAPT LDVVRFQKAW QTLAQVTPIL RTRILAGLDT
SDVSLQVVVR GSITWQYGAD SGTLSDYVAQ DRKSGMRLGQ PLVRFGLVRN SSEQFFIWTA
HHSVYDGWSV SLMYQHLYDI YFDQRIPSTI PYARFIRYLI RHDDAASEKY WRSQLQGEVV
SNWPPLPRAD YQPRPQQRYT CDIILPDHTM NDRVNSLLPS VLRAAWGVTM SKYTGQGDVV
FGVTLLGRNA PVSQITEMTG PTITTVPVRI HLDGPQPLTI NQFLQNVQKQ AADMINYEHA
GLQVIKKLVP ELNSSLELRN LLVIQPASET DGTAFPGLDP LPVDLEGFDS YGLTIECSIL
SGLVKVEARY DENVIATPQL KRTIRTFEHV VKQLLDVRNS VYRLEEMSWL SDYDEEAIAN
WSKATPIRVE RCIHELVQEQ TKLRPNATAI CAWDGNLTYA ELDMQATWLA RYLTSLGACS
QRMVGICMDK SKWAGVSMLA VLKAGAVLVP LGVNHPEARI KAMVDDTDTQ IILVDEKQRD
RLSIQGVRLI TVDADILKKL PVLAEKEELL GSVNPDDAAW VIYTSGSTGK PKGVVLQHVA
LCSSIQAHGA RFGMGTSTRM LQFAAHTFDA CIQDYFTTLS WGGVVCVPSE NDRMSDLTTA
MCQMKVTFAT LTSTVARLID PHKVPSMQKL ALVGEPVKAD VVKQWLGHTI VLNAYGPSEC
SIHSSCGEPL ADSTKSAVIG TGMGTRLWVV DVDYNQLCPI GAPGELLIEG PLLAREYLND
PRKTKAAFVS DPRFAQKFGL APGTRMYRTG DLVKQNEDSS ITHLGRRDTQ IKIRGQRVEV
GEIEFQIAQH PQVRTVAVEL LEQDSNGSQV ILTAVIEFTE DSEYRNGPVT SSGLLTLTPS
LSLAFEMLRG ALFQVLPSYM LPSMYVPIVD MPMNVNGKLD RRAVRDLLQA MTPDVRQQYL
SASDHKVAPS TREECLVHSL WTEALSLSFS QVGIYDNFFQ IGGDSVVAMR MVATESAREL
QLTVADLFQH PRLIELAELL AKRSVDKKVE ADPEPFSLWL EPQIGSEQQQ EKLTMVAKQC
GISVNHVEDV YPCTPLQVGL MAITARQPLA YIDRQVYKLA DTIDLDRFQA AWRALSDATP
ILRTRIITSE GPQSFLQVVV GGCDPWRDSN DLEDYMASDR DVGIALGKPL VRMGLVRERN
SEERYFVWTA HHSVYDGTSA LLMYQQLASI YFHGSLLPTA PFTRFIRYLA RKEVIAAESA
AYWADQLQGE VMANWPPLPR IDYQPKPQHE MTQIFRLPQF ESRSVVTISN VIRAAWALVM
AQRTGHSDVV FAVTVSGRNA PISQVDSIIA PTISTVPVRV QIDWTQDVAG FLFAIQNQAA
QMIDYEHTGL RAIKALVPEL GPTLDIRNVL VVQTAEERGA ADHFPGIEAL PQGKENFDSY
GLLTECTLGT DGEVRIDFRY DDNVIPSSSI KRISAQFAHL VQQLCGNATS TLHRLNELVL
IAPEDQEQIM KWNPMLPPRV DSCIHELFYK QVMARPQAEA VSGWDGELSY SDLADESIRL
AYQLISLGIG PEMKVGLCID KSKWAIIAIM SILFAGGVVV PLGVTHPLPR LDVVIEDASI
DLILVDQHQR KRLAALSQNV KLITVNDALL RTLPVHTEPP VTGVVSRNAA WIIYTSGSTG
TPKGVVLEHG GCCTSMRTQG KKMNLSAETR ALQFTPFTFD VSISDVSATL IYGGCICVIS
ESDRVNNLPG AIREMKVNFA SLTPTVAQML SPAELPSLKT LALTGEAVKP EVVELWMNSV
ALYDTYGPSE GSVCTCNGPL SSPDQADNIG FPMSTLHWVT QLHNHNQLCP IGAPGELLIE
GPLLARGYLN QARTKESFVN DPAFTKQQTG LPSARHIYRT GDLVRQNEDG SFIYLGRRDD
QIKIRGQRVE VGEIEYQIVC ELPGTHSAAV AMLQDGKNIS LIAIVDFKSD SEHYPGELES
LGTLAPTPQL RAAFNELRQS LTKLLPSYMV PAIFVPVVQM PTNISGKLDR LGVRALLRAI
PSDHLARYMI DETLPSETPS TKMEKVIQSL WAEALDIPMD NISAHDNFFQ IGGDSVTAMR
IVAATTRTNQ LQLTVSDIFQ NPKLSDLASV MTEHRKNHFD VMDEDPEPFS LWEAVISDNS
NEQKRQIEAI AQQCNVSVDD IEDIYPCTAL QEGLLAVTAR QTSAYVSRQA YVLSDQIDIS
RFKEAWRKLV AGIHILRTRA VVGPDSLLQV VVRDEITWRH GSNLEDYIQQ DKEEGIRLGQ
PLSRYGLVQL PSGEQVFVWT AHHSIYDGWT IRLMCRQLIS LYRQEEDIST SIPYSRFIQY
LTQINIEDSI EYWREQLRGE SVTANWPSLP QPNYEPRPRH LLRKHISLPR TENQGIVMSN
ILRAAWGLVM IQYSGENDVV YAANLSGRNV PVRDVAEICA PTITTVPIRL RLDHTSTQTV
GDFLQNIQQQ AIEMINHEHT GLQVIKSLAP ELSDSVLKLR NLLVIQPAAE SDTHLDFPGI
ELVPSDIADF DAYGVNIECT LGQEIAVEAR YDENVVETPY MNGVLDQFVY IVGLLCDPSI
SRWNATVPER VTKCIHELVQ EQALARPTAL AVQAWDGKLT YGELDNLANR LAHQLVSFGI
GSLPDQMVGV CMEKSLFAVV AMLAVLKAGG VVVPLGVTHP ITRLDTIIHD TGITVLLVDA
SQDERLAELS PTRILVNSDH LYHYLPARTQ PPKTPVNHMD AAWVIYTSGT TGTPKGAVSE
HGTLSTSIKA HGARYGFGHH TRKLNYAAHT FDGTIEDFFT TLSWGGVCCI PSEEDRMDKY
KLMEFMNLTK VNSAAMTYTV ASLLSPRDLP TLHTLVLGGE PATIDVVSTW MTEVNLFNCY
GPSECSIFSA AAGPTKNTNE LHNIGFPIGT RLWVADIENY HKLAPIGAPG ELLIEGPQLA
RGYLNDESKT SAAFIVDPAF TTHFKLPLGT RMYRSGDIVR QKNDGSLVYV ARRDMQVKIR
GQRVEIGEIE SQISQHISEA RTIAVELLKL GTQSQPVLVA AVEFADGSQY HTGDVTSFGM
LAPTEAIREA FIKLRGTLFQ VLPGYMVPSA YLTIAEMPRN ISGKLDRKTL RTMLEAIPAD
AIQQYLDGEA KTLPSTQVEL QLQALWAEAL GISVDGVGAH DNFFQLGGDS VAAMRIVAMS
QAREMGLSVA DIFAYPRLSE LAVILDGRKN SNEVFYSDPE PFALWPRATN KVLDENTLLA
DIASKCNVTV NQIEDIYPCT PLQEGMIAIT ARQSAAYVSR QIYALDTTVI ELGKFQRAWQ
VLANATPILR TRLVITQNGQ SMQVVLRDTI AWRHSTDLDA YVNEDRAEGI SLGQPLLRYS
LVKQITGECF FVWTAHHSIY DGWTMRSICQ RLVEMYNNID NSSYQMPQSV PYSRFIHYLT
QSDKSAAATF WRQQLHGDIM ADWPSLPSID YQPKPQHRDR KTIRVAGSTS KNILTSNILR
AAWALLMSQY TGHPDVVFAA SVSGRNAPVW QIGEIAGPTL TTVPVRVQAK PGMTVRQFIQ
EVQEQSTAMI RFEHTGLQNI KALVPEAAMA LELRNVLVVQ IAEESDHRID FPGLEALPMP
FEDFDSFGIH LECTPGLDDI EVEARYDVNI VSAPHMKRVL NQFEYVVQKF HDSEYSDFSL
QSIQLNPHDE RQILEWNATV PSHTERCVHN LVDDHVAARP MAPAICGWDG DLTYRELSRI
ATSLAFHLQH ELGVGPEQKV GVCMDKSKWA VVAMLAVMYA GGVVVPLGVA HPLTRIRGIL
IDSASSVVLV DATQRERLVD LHTSLICVDA KLIARLSSQN QKQNQTQKLQ VEVTPGNLAW
VVYTSGSTGK PKGVMLEHRA LSTALQAHGS AFGMDTNTRT IQFAAHTFDA AIQDIFTTFS
KGGCVCIPSE HDRVNNLTKA MASMNVNFAN FTSTVASMLV PEELPSLKTM ILAGEAVTPT
AVGLWSQHVT IFNSYGPSEC SINSSCSKPV KEVSQASNVG LPLSCCFWVT NTTDYNSLCP
IGAPGELLIE GPIQARGYLN DKEQTNKSFV TDPGFTKKLG LSGRRMYRTG DLVRQNADGT
LTYLGRQDLQ VKIRGQRVEI GEIEYQIKKK LLGARTVAVE KIEQGGHSEQ TRLVTMMDFK
DTSEHSHNPD ILASGALSPT PKLQTAFEKL RQSLSEVLPS YMVPTFYVPV AQMPVNASNK
LDRRAVKAVL ASLTPDALQQ YLPGGTDTKQ APDTDLGRLI QGLWADALGI STDTISMTDN
IFHLGGDSVT AMRIVAAAYS HELQLTVTDI FQHPQLADLV NTLSNRSLER NTEIQEDPMA
FELWEEAASC STEERKRLLT EVAAQCGVAV SHIEDVYPST PLQEGLMAIT ARQPAAYVSR
QVYTLAKTVD QLKFKMAWQA LSSEAHILRT RLLVAPHGLQ VVVNDRIDWH HGTDLENYLQ
ADRRAGMSPG KPLVRYGLIK QPSGETFFVW TSHHSLYDGW TLRSLGKRLL DLYNDGSPQS
FVPFSRFIRY LQFGRPGNDD TATYWRNELE GDIVTDWPSL PRSDYQPLPR DNFSRAITLP
DSHHSGSVVM SNVIRAAWAL VMSQYAGHND VAFAATVSGR NAPVWQIEDI PAPTITTVPL
RISVDPMQTV AEFLDTVQQQ AVRMIDYEHT GLQGIKALAP DLGPAIDLRN LLVVQPAADS
DSNVQLDFPG LGSVSMPIEP FNSYGLTVEC KLASHEIVVD VHYDKDVISS AQLKRVIDFF
ACVVQRILTQ SPRSYRIQEI VAIGEEDLQQ VLAWNSTIPP NVDKCIHEMV QAQVKKSPAA
LAISAWDGDL TYEEFFKSSA RLAHHLVALG VNTGSNIGIC MDKSKWGPVS MLSIMQAGAA
IMPLGTSHPL ARIETIVRNS EASVIIVDEK QRQRLDQLYT ETSLTLVTVD SKFFKQLPAQ
TKAPSTGVRP SDASWLIHTS GSTGVPKGVI IDHVTMSTSL RAQGSWLGLN QKSRFLQFSN
YTFDNVITDT FATTVFGGCV CVPSEDARMN NLPGFMATAN VNVAMLTSTV ARQISPSQVP
SLHTLILTGE PVRADVVSTW LGHADIYNAY GPTEGSMSTC TKPMMRSDQV SNIGYPLATR
AWITQPDHIQ LSPIGAPGEL FIEGPLLARG YLNNPEMTRD SFIINPEFTK RLGLENRRVY
RTGDLVRQNE DGSLIYLGRR DLQVKIRGQR VEVGEIELQI IKHTPGAELV AVELIQQKDT
KEEKRNLIAA IEFAKDSEHC HGSQNTPGPQ ILAPTDALRD DFARLRGLLY QVLPSYMIPS
AFIPTTNLDR NLSGKLDRKG LRGLLEALSS QQLRQYSASG GSKVNPSTTM ERQLQTLWAE
ALGIPADQVG AHDNFFQIGG DSMVAMRVVA ASHSKDLNLR VNDIFQHSCL SDLAVVLTDR
LAHNFNGGQD GHAPFSLIKT DDIDDFLQQI ASSVVGCAIQ DIVDILPTTD FQSSIIDTAL
AAPKSGTSHF LLDGNGPCDT RALKKSCLEL IQATDTLRTG YVFDQGNLLQ VIQAYFEPEI
KIYETDSTIE AVTEDIVSRD MYQPIGLGRP FTQIAIIRET ATLKHRVLLR LTHAEYDAHS
MGSIWQNLRS LYEGGSTRPQ AKFSDFLYNQ RQSINADTYD YWRDLLKGSS MPAINLSAKK
IGQYPSKVNQ DLFRTIETPD LMVEGRTSAM LVKSAWSLVL SQFLRVNDVV FADTVSTRTT
VDSSLMDAMG CCVTLIPFRV TLEQQWTIKD LLDNVRDQQS QSMQHSQLGF REILRECTDW
PASTRFTSAL NHISSGPESS IFSMRGVEYS ISEMEIKDPL WEIDVGITTI QRGSELEIRL
SYLPANISES VATSLLDALH NTLQFIHNNP LSPVKQVLSF HTDMKIQNGS SN
