ID ACVA_EMENI Reviewed; 3770 AA.
AC P27742; C8VHS8; Q4J6A7; Q4J6A8; Q5BA09;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 26-MAY-2009, sequence version 2.
DT 27-NOV-2024, entry version 155.
DE RecName: Full=N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase;
DE EC=6.3.2.26 {ECO:0000269|PubMed:2645274};
DE AltName: Full=Delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase {ECO:0000303|PubMed:2061333};
DE Short=ACV synthetase {ECO:0000303|PubMed:2061333};
DE Short=ACVS {ECO:0000303|PubMed:2061333};
GN Name=acvA {ECO:0000303|PubMed:2061333}; ORFNames=AN2621;
OS Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 /
OS M139) (Aspergillus nidulans).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Nidulantes.
OX NCBI_TaxID=227321;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 547-561; 944-979;
RP 1928-1944; 2396-2419 AND 3102-3118, AND GLYCOSYLATION.
RC STRAIN=G191;
RX PubMed=2061333; DOI=10.1016/s0021-9258(18)98948-9;
RA Maccabe A.P., van Liempt H., Pallissa H., Unkles S.E., Riach M.B.R.,
RA Pfeifer E., von Doehren H., Kinghorn J.R.;
RT "Delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase from
RT Aspergillus nidulans. Molecular characterization of the acvA gene encoding
RT the first enzyme of the penicillin biosynthetic pathway.";
RL J. Biol. Chem. 266:12646-12654(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX PubMed=16372000; DOI=10.1038/nature04341;
RA Galagan J.E., Calvo S.E., Cuomo C., Ma L.-J., Wortman J.R., Batzoglou S.,
RA Lee S.-I., Bastuerkmen M., Spevak C.C., Clutterbuck J., Kapitonov V.,
RA Jurka J., Scazzocchio C., Farman M.L., Butler J., Purcell S., Harris S.,
RA Braus G.H., Draht O., Busch S., D'Enfert C., Bouchier C., Goldman G.H.,
RA Bell-Pedersen D., Griffiths-Jones S., Doonan J.H., Yu J., Vienken K.,
RA Pain A., Freitag M., Selker E.U., Archer D.B., Penalva M.A., Oakley B.R.,
RA Momany M., Tanaka T., Kumagai T., Asai K., Machida M., Nierman W.C.,
RA Denning D.W., Caddick M.X., Hynes M., Paoletti M., Fischer R., Miller B.L.,
RA Dyer P.S., Sachs M.S., Osmani S.A., Birren B.W.;
RT "Sequencing of Aspergillus nidulans and comparative analysis with A.
RT fumigatus and A. oryzae.";
RL Nature 438:1105-1115(2005).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX PubMed=19146970; DOI=10.1016/j.fgb.2008.12.003;
RA Wortman J.R., Gilsenan J.M., Joardar V., Deegan J., Clutterbuck J.,
RA Andersen M.R., Archer D., Bencina M., Braus G., Coutinho P., von Dohren H.,
RA Doonan J., Driessen A.J., Durek P., Espeso E., Fekete E., Flipphi M.,
RA Estrada C.G., Geysens S., Goldman G., de Groot P.W., Hansen K.,
RA Harris S.D., Heinekamp T., Helmstaedt K., Henrissat B., Hofmann G.,
RA Homan T., Horio T., Horiuchi H., James S., Jones M., Karaffa L.,
RA Karanyi Z., Kato M., Keller N., Kelly D.E., Kiel J.A., Kim J.M.,
RA van der Klei I.J., Klis F.M., Kovalchuk A., Krasevec N., Kubicek C.P.,
RA Liu B., Maccabe A., Meyer V., Mirabito P., Miskei M., Mos M., Mullins J.,
RA Nelson D.R., Nielsen J., Oakley B.R., Osmani S.A., Pakula T., Paszewski A.,
RA Paulsen I., Pilsyk S., Pocsi I., Punt P.J., Ram A.F., Ren Q., Robellet X.,
RA Robson G., Seiboth B., van Solingen P., Specht T., Sun J.,
RA Taheri-Talesh N., Takeshita N., Ussery D., vanKuyk P.A., Visser H.,
RA van de Vondervoort P.J., de Vries R.P., Walton J., Xiang X., Xiong Y.,
RA Zeng A.P., Brandt B.W., Cornell M.J., van den Hondel C.A., Visser J.,
RA Oliver S.G., Turner G.;
RT "The 2008 update of the Aspergillus nidulans genome annotation: a community
RT effort.";
RL Fungal Genet. Biol. 46:S2-13(2009).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=2645274; DOI=10.1016/s0021-9258(19)84905-0;
RA van Liempt H., von Doehren H., Kleinkauf H.;
RT "delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase from
RT Aspergillus nidulans. The first enzyme in penicillin biosynthesis is a
RT multifunctional peptide synthetase.";
RL J. Biol. Chem. 264:3680-3684(1989).
RN [5]
RP FUNCTION.
RX PubMed=8277946; DOI=10.1007/bf00277348;
RA Brakhage A.A., Browne P., Turner G.;
RT "Analysis of the regulation of penicillin biosynthesis in Aspergillus
RT nidulans by targeted disruption of the acvA gene.";
RL Mol. Gen. Genet. 242:57-64(1994).
RN [6]
RP FUNCTION.
RX PubMed=9003303; DOI=10.1007/s004380050312;
RA Kennedy J., Turner G.;
RT "delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase is a rate
RT limiting enzyme for penicillin production in Aspergillus nidulans.";
RL Mol. Gen. Genet. 253:189-197(1996).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of penicillin, the world's most
CC important antibiotic (PubMed:2645274, PubMed:8277946, PubMed:9003303).
CC The trimodular NRPS acvA produces the tripeptide N-[(5S)-5-amino-5-
CC carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) via
CC condensation of the 3 residues L-2-aminoadipate, L-cysteine and L-
CC valine (PubMed:2645274). The precursor amino acids for penicillin
CC biosynthesis are withdrawn from the vacuolar amino acid pool by the
CC MFS-type transporter penV (By similarity). Each of the constituent
CC amino acids of the tripeptide ACV are activated as aminoacyl-adenylates
CC with peptide bonds formed through the participation of amino acid
CC thioester intermediates (PubMed:2645274). The penicillin biosynthesis
CC occurs via 3 enzymatic steps, the first corresponding to the production
CC of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-
CC valine (LLD-ACV or ACV) by the NRPS acvA. The tripeptide ACV is then
CC cyclized to isopenicillin N (IPN) by the isopenicillin N synthase ipnA
CC that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side
CC chain is exchanged for phenylacetic acid by the isopenicillin N
CC acyltransferase penDE to yield penicillin in the peroxisomal matrix (By
CC similarity). {ECO:0000250|UniProtKB:P19787, ECO:0000269|PubMed:2645274,
CC ECO:0000269|PubMed:8277946, ECO:0000269|PubMed:9003303}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-2-aminoadipate + L-valine + L-cysteine + 3 ATP + H2O = N-
CC [(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine + 3 AMP + 3
CC diphosphate + 3 H(+); Xref=Rhea:RHEA:23196, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:35235, ChEBI:CHEBI:57762, ChEBI:CHEBI:58572,
CC ChEBI:CHEBI:58672, ChEBI:CHEBI:456215; EC=6.3.2.26;
CC Evidence={ECO:0000269|PubMed:2645274};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23197;
CC Evidence={ECO:0000269|PubMed:2645274};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Note=Binds 3 phosphopantetheines covalently. {ECO:0000255};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P19787};
CC -!- PATHWAY: Antibiotic biosynthesis; penicillin G biosynthesis; penicillin
CC G from L-alpha-aminoadipate and L-cysteine and L-valine: step 1/3.
CC {ECO:0000269|PubMed:2645274}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P19787}. Vacuole membrane
CC {ECO:0000250|UniProtKB:P19787}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P19787}. Note=Loosely attached to the vacuoles.
CC {ECO:0000250|UniProtKB:P19787}.
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. GliP has the following
CC architecture: A-T-C-A-T-C-A-T-E-TE. {ECO:0000250|UniProtKB:P19787}.
CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:2061333}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; AH000059; AAA03914.1; -; Genomic_DNA.
DR EMBL; AH000059; AAA03916.2; -; Genomic_DNA.
DR EMBL; X54853; CAA38631.1; -; Genomic_DNA.
DR EMBL; AACD01000045; EAA62968.1; -; Genomic_DNA.
DR EMBL; BN001306; CBF84349.1; -; Genomic_DNA.
DR PIR; A40889; A40889.
DR RefSeq; XP_660225.1; XM_655133.1.
DR SMR; P27742; -.
DR STRING; 227321.P27742; -.
DR ESTHER; emeni-acvs; Thioesterase.
DR ESTHER; emeni-q4j6a7; Thioesterase.
DR GlyCosmos; P27742; 16 sites, No reported glycans.
DR EnsemblFungi; CBF84349; CBF84349; ANIA_02621.
DR GeneID; 2874260; -.
DR KEGG; ani:ANIA_02621; -.
DR VEuPathDB; FungiDB:AN2621; -.
DR eggNOG; KOG1176; Eukaryota.
DR eggNOG; KOG1178; Eukaryota.
DR HOGENOM; CLU_000022_0_0_1; -.
DR InParanoid; P27742; -.
DR OMA; HEAYHTE; -.
DR OrthoDB; 2315757at2759; -.
DR UniPathway; UPA00149; UER00239.
DR Proteomes; UP000000560; Chromosome VI.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005774; C:vacuolar membrane; ISS:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050564; F:N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase activity; IDA:AspGD.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0042318; P:penicillin biosynthetic process; IDA:AspGD.
DR GO; GO:0019748; P:secondary metabolic process; NAS:AspGD.
DR CDD; cd17648; A_NRPS_ACVS-like; 2.
DR CDD; cd19543; DCL_NRPS; 1.
DR CDD; cd19534; E_NRPS; 1.
DR CDD; cd19539; SgcC5_NRPS-like; 1.
DR FunFam; 3.30.300.30:FF:000010; Enterobactin synthetase component F; 1.
DR FunFam; 3.30.559.30:FF:000069; N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase; 2.
DR FunFam; 1.10.1200.10:FF:000016; Non-ribosomal peptide synthase; 1.
DR FunFam; 3.40.50.980:FF:000001; Non-ribosomal peptide synthetase; 3.
DR FunFam; 2.30.38.10:FF:000001; Non-ribosomal peptide synthetase PvdI; 2.
DR FunFam; 1.10.1200.10:FF:000005; Nonribosomal peptide synthetase 1; 1.
DR FunFam; 3.30.300.30:FF:000056; Putative peptide synthase; 1.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.40.50.980; -; 6.
DR Gene3D; 1.10.1200.10; ACP-like; 3.
DR Gene3D; 3.40.50.1820; alpha/beta hydrolase; 1.
DR Gene3D; 3.30.559.10; Chloramphenicol acetyltransferase-like domain; 3.
DR Gene3D; 3.30.559.30; Nonribosomal peptide synthetase, condensation domain; 4.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase_fold.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR025110; AMP-bd_C.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig_com.
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 InterPro; IPR001031; Thioesterase.
DR NCBIfam; TIGR01733; AA-adenyl-dom; 3.
DR PANTHER; PTHR44845; CARRIER DOMAIN-CONTAINING PROTEIN; 1.
DR PANTHER; PTHR44845:SF8; N-(5-AMINO-5-CARBOXYPENTANOYL)-L-CYSTEINYL-D-VALINE SYNTHASE; 1.
DR Pfam; PF00501; AMP-binding; 3.
DR Pfam; PF13193; AMP-binding_C; 2.
DR Pfam; PF00668; Condensation; 3.
DR Pfam; PF00550; PP-binding; 3.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF56801; Acetyl-CoA synthetase-like; 3.
DR SUPFAM; SSF47336; ACP-like; 3.
DR SUPFAM; SSF53474; alpha/beta-Hydrolases; 1.
DR SUPFAM; SSF52777; CoA-dependent acyltransferases; 7.
DR PROSITE; PS00455; AMP_BINDING; 3.
DR PROSITE; PS50075; CARRIER; 3.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 3.
PE 1: Evidence at protein level;
KW Antibiotic biosynthesis; ATP-binding; Cytoplasm; Direct protein sequencing;
KW Glycoprotein; Ligase; Membrane; Multifunctional enzyme; Nucleotide-binding;
KW Phosphopantetheine; Phosphoprotein; Reference proteome; Repeat; Vacuole.
FT CHAIN 1..3770
FT /note="N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine
FT synthase"
FT /id="PRO_0000193057"
FT DOMAIN 845..922
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1928..2005
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3015..3090
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..50
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 326..738
FT /note="Adenylation (A) domain 1"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 946..1398
FT /note="Condensation (C) domain 1"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 1417..1827
FT /note="Adenylation (A) domain 2"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 2020..2460
FT /note="Condensation (C) domain 2"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 2502..2907
FT /note="Adenylation (A) domain 3"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 3107..3523
FT /note="Epimerase (E) domain"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT REGION 3554..3756
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:P19787, ECO:0000255"
FT MOD_RES 882
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1965
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3050
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT CARBOHYD 88
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 309
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 570
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 596
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 638
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 639
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 655
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 787
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1256
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1402
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1545
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1735
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 2410
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 3130
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 3298
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 3332
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CONFLICT 1941
FT /note="W -> S (in Ref. 1; AAA03914/CAA38631/AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 2177..2178
FT /note="NE -> KQ (in Ref. 1; AAA03914/CAA38631)"
FT /evidence="ECO:0000305"
FT CONFLICT 2335
FT /note="A -> P (in Ref. 1; AAA03914/CAA38631)"
FT /evidence="ECO:0000305"
FT CONFLICT 2869
FT /note="S -> C (in Ref. 1; AAA03914/CAA38631)"
FT /evidence="ECO:0000305"
FT CONFLICT 3116
FT /note="T -> I (in Ref. 1; AAA03914/CAA38631/AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 3139
FT /note="E -> D (in Ref. 1; CAA38631)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 3770 AA; 422502 MW; B31873DD4106D7B0 CRC64;
MSPPGLLSED GPGYSGGYAD PTVPKVNWKQ SNGKSAGGNG DVDAGNGNID PSKSGVGVQV
CFAGGLEGWK AGISKITERC DLSSIATNST KYQLAVTGFS DGPDDYNEYS VPFPSEVLVA
MEEMCLARDI SMRSVIQFAV HYVLKGFGGG SHTVAASIDV GDDPNNIATS YTITPSIVCH
ESRQGQTVMQ EIQSMEKLNQ LRKQEMHPGE AGLSLIRMGL FDILVIFADA NKCEGLIAGL
PLAVMVCEGG GRLQVRIHFS GSLFRQKTLV DIAEALNVLF AKAASGGATP VRDLELLSAE
QKQQLEEWNK TDGEYPECKR LNHLIEEATQ LHEDKVAIVY KRRQLTYGEL NAQANCFAHY
LRSIGILPEQ LVALFLEKSE NLIVTILGIW KSGAAYVPID PTYPDERVRF VLEDTQAKVI
IASNHLAERL QSEVISDREL SIIRLEHCLS AIDQQPSTFP RANLRDPSLT SKQLAYVTYT
SGTTGFPKGI LKQHTNVVNS ITDLSARYGV TGDHHEAILL FSAYVFEPFV RQMLMALVNG
HLLAMVDDAE KYDAEKLIPF IREHKITYLN GTASVLQEYD FSSCPSLKRL ILVGENLTES
RYLALRRHFK NCILNEYGFT ESAFVTALNV FEPGSARNNT SLGRPVRNVK CYILNKSLKR
VPIGATGELH IGGLGISKGY LNRPDLTPQR FIPNPFQTDH EKELGLNQLM YKTGDLARWL
PNGEIEYLGR ADFQIKLRGI RIEPGEIEST LAGYPGVRTS LVVSKRLRHG EKETTNEHLV
GYYVGDNTSV SETALLQFLE LKLPRYMIPT RLVRVSQIPV TVNGKADLRA LPSVDLIQPK
VSSCELTDEV EIALGKIWAD VLGAHHLSIS RKDNFFRLGG HSITCIQLIA RIRQQLGVII
SIEDVFSSRT LERMAELLRS KESNGTPDER ARPQLKTVAG EVANANVYLA NSLQQGFVYQ
FLKNMGRSEA YVMQSVLRYD VNINPDLFKK AWKQVQHMLP TLRLRFQWGQ DVLQVIDEDQ
PLNWWFLHLA DDSALPEEQK LLELQRRDLA EPYDLAAGSL FRIYLIEHSS TRFSCLFSCH
HAILDGWSLP LLFRKTHGTY LHLLHGHSLR TLEDPYRQSQ QYLQDHREDH LRYWAGIVNQ
IEERCDMNAL LNERSRYKIQ LADYDKVEDQ QQLTLTVPDA SWLSKLRQTC SAQGITLHSI
LQFVWHAVLH AYGGGTHTVT GTTISGRNLP VSGIERSVGL YINTLPLVIN QLAYKNKTVL
EAIRDVQAIV NGMNSRGNVE LGRLQKNELK HGLFDSLFVL ENYPILDKSE EMRQKSELKY
TIEGNIEKLD YPLAVIAREV DLTGGFTFTI CYARELFDEI VISELLQMVR DTLLQVAKHL
DDPVRSLEYL SSAQMAQLDA WNATDAEFPD TTLHAMFEKE AAQKPDKVAV VYEQRSLTYR
QLNERANRMA HQLKSDISPK PNSIIALVVD KSEHMIATIL AVWKTGGAYV PIDPEYPDDR
IRYILEDTSA IAVISDACYL SRIQELAGES VRLYRSDIST QTDGNWSVSN PAPSSTSTDL
AYIIYTSGTT GKPKGVMVEH HGVVNLQISL SKTFGLRDTD DEVILSFSNY VFDHFVEQMT
DAILNGQTLV MLNDAMRSDK ERLYQYIETN RVTYLSGTPS VISMYEFSRF KDHLRRVDCV
GEAFSQPVFD QIRDTFQGLI INGYGPTEIS ITTHKRLYPF PERRTDKSIG QQIGNSTSYV
LNADMKRVPI GAVGELYLGG EGVARGYHNR PEVTAERFLR NPFQTDSERQ NGRNSRLYRT
GDLVRWIPGS NGEIEYLGRN DFQVKIRGLR IELGEIEAVM SSHPDIKQSV VIAKSGKEGD
QKFLVGYFVA SSPLSPGAIR RFMQSRLPGY MIPSSFIPIS SLPVTPSGKL DTKALPTAEE
KGAMNVLAPR NEIESILCGI WAGLLDISAQ TIGSDSDFFT LGGDSLKSTK LSFKIHEVFG
RTISVSALFR HRTIESLAHL IMNNVGDIQE ITPVDYDNRR KIAVSPAQER LLFIHELEGG
GNAYNIDAAF ELPPYIDQSR VEEALYTILS RHEALRTFLL RDQATGTFYQ KILTTDEAKC
MLIIEKSAVS TIDQIDSIVG RLSQHIFRLD SELPWLAHIV THKTGNLYLT LSFHHTCFDA
WSLKIFEREL RVFCASNEKG GNMPILPMPQ VQYKEYAEHH RRRLGKNQIQ KLSDFWLQRL
DGLEPLQLLP DYPRPAQFNY DGGDLSVILD GVVLETLRGI AKDHGVTLYA VLLAVYCLML
STYTHQVDIA VGVPISHRTH PLFQSIVGFF VNMVVVRVDV KDFAVHDLIR RVMKALVDAQ
LHQDMPFQDV TKLLRVDNDA SRHPLVQTVF NFESDMDKEF ETTPSIQDTA TIAPYQSVQR
IKSVAKFDLN ATATESGSAL KINFNYATSL FRKETIQGFL ETYRHLLLQL SYLGSQGLKE
DTKLLLVRPE EMSGPHLPLA GLSNGAETLE AISLSRAFEF EAFRVPDRAA VVQGDKSLSY
TELNKRANQL ARYIQSVAHL RPDDKVLLIL DKSIDMIICI LAIWKTGSAY VPLDPSYPKE
RVQCISEVVQ AKILITESRY ASAWGSQTST ILAIDSPKVS NMVNNQATHN LPNIAGIKNL
AYIIFTSGTS GKPKGVLVEQ GGVLHLRDAL RKRYFGIECN EYHAVLFLSN YVFDFSIEQL
VLSIMSGHKL IIPEGEFVAD DEFYITANGQ RLSYLSGTPS LLQQIDLARL NHLQVVTAAG
EQLHAAQFNK LRSGFRGPIY NAYGITETTV YNIVSEFSAQ SQFENALREL LPGTRAYLLN
HATQPVPMNA VGELYLAGDC VARGYLNQPV LTGDRFIQNP FQTEQDIASG SYPRLYRTGD
LFRCRLDRQH QPYLEYLGRA DLQVKIRGYR IEPSEVQNVL ASCPGVRECA VVAKYENTDA
YSRIAKFLVG YYTPDTETVS DSSILAHMKS KLPAYMVPKY LCRLEGGLPV TINGKLDVRK
LPDIGNPQHQ ISYNPPRDVL EADLCRLWAS ALGTERCGID DDLFRLGGDS ITALHLAAQI
HHQIGRKVTV RDIFDHPTIR GIHDNVMVKL VPHNVPQFQA EQQTVLGDAP LLPIQTWFLS
KSLQHPSHWN HTFYLRTPEL DVTTLSTAVA ELQLYHDAFR MRLRQIDGRT VQCFADDISP
VQLRVLNVKD VDGSAAIDQQ LQKYQSDFDL EKGPICAAAY LHGYEDRSAR VWFSVHHIII
DIVSWQILAR DLQILYEGGT LGRKSSSVRQ WAEALQSYQG SASERAYWEG LLAQTAANIS
ALPPVTGTRT RLARTWSDDR TVILLNEASN QNASIQDLLL AAVGLALQQV TPGSPSMITL
EGHGREEIVD PTLDLSRTLG WFTSMYPFEI PPLNVETLSQ GIASLRECLR QVPARGIGFG
SLYGYCKHQM PQVTFNYLGQ LTSKQSITDQ WALAVGDGEM QYGLTTSPAD RDQSSFAVDI
TASCVNGALS VEMNSAWSLE KSMRFISRIE EVLNMILSGT LAQQATPVLT PQVFNEEMYT
PYFEFSKTPR RGPILFLLPP GEGGAESYFN NIVKHLPTTN MVVFNNYYLH SKSLNTFEKL
AEMYLGHIRQ IQPDGPYHFI GWSFGGTIAM EISRQLVGLG STIGLLGIID TYFNVPGATR
AIGLGDTEVL DPIHHISQPE PADFQCLPAS TDYIILFKAT RVNDKFQSEN QRRLYEYYDK
TLLNDLDWLL PGASNIHLVR LEEDTHFSWA TNPRQIAHVC STIEKFLARY
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