ACVA_PENCH
ID ACVA_PENCH Reviewed; 3746 AA.
AC P19787; P26046;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase {ECO:0000303|PubMed:21889568};
DE Short=ACV synthetase {ECO:0000303|PubMed:21889568};
DE Short=ACVS {ECO:0000303|PubMed:21889568};
DE EC=6.3.2.26 {ECO:0000269|PubMed:1368505, ECO:0000269|PubMed:19686863, ECO:0000269|PubMed:21889568, ECO:0000269|PubMed:9266851, ECO:0000269|PubMed:9355751};
DE AltName: Full=Delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase {ECO:0000303|PubMed:2118102};
DE AltName: Full=Nonribosomal peptide synthetase acvA {ECO:0000303|PubMed:2118102};
DE AltName: Full=Penicillin biosynthetis cluster p rotein acvA {ECO:0000303|PubMed:1368505};
GN Name=acvA {ECO:0000303|PubMed:2118102};
GN Synonyms=pcbAB {ECO:0000303|PubMed:2129535};
OS Penicillium chrysogenum (Penicillium notatum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium;
OC Penicillium chrysogenum species complex.
OX NCBI_TaxID=5076;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=AS-P-78;
RX PubMed=2129535; DOI=10.1016/s0021-9258(17)46231-4;
RA Diez B., Gutierrez S., Barredo J.L., van Solingen P., van der Voort L.H.M.,
RA Martin J.F.;
RT "The cluster of penicillin biosynthetic genes. Identification and
RT characterization of the pcbAB gene encoding the alpha-aminoadipyl-
RT cysteinyl-valine synthetase and linkage to the pcbC and penDE genes.";
RL J. Biol. Chem. 265:16358-16365(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND IDENTIFICATION.
RC STRAIN=CMI 314652;
RX PubMed=2118102; DOI=10.1002/j.1460-2075.1990.tb07461.x;
RA Smith D.J., Earl A.J., Turner G.;
RT "The multifunctional peptide synthetase performing the first step of
RT penicillin biosynthesis in Penicillium chrysogenum is a 421,073 dalton
RT protein similar to Bacillus brevis peptide antibiotic synthetases.";
RL EMBO J. 9:2743-2750(1990).
RN [3]
RP INDUCTION.
RX PubMed=3096965; DOI=10.1128/jb.168.2.947-952.1986;
RA Revilla G., Ramos F.R., Lopez-Nieto M.J., Alvarez E., Martin J.F.;
RT "Glucose represses formation of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-
RT valine and isopenicillin N synthase but not penicillin acyltransferase in
RT Penicillium chrysogenum.";
RL J. Bacteriol. 168:947-952(1986).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=1368505; DOI=10.1038/nbt0190-39;
RA Smith D.J., Burnham M.K., Edwards J., Earl A.J., Turner G.;
RT "Cloning and heterologous expression of the penicillin biosynthetic gene
RT cluster from penicillum chrysogenum.";
RL Biotechnology (N.Y.) 8:39-41(1990).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=1899377; DOI=10.1002/j.1460-2075.1991.tb07971.x;
RA Mueller W.H., van der Krift T.P., Krouwer A.J., Woesten H.A.,
RA van der Voort L.H., Smaal E.B., Verkleij A.J.;
RT "Localization of the pathway of the penicillin biosynthesis in Penicillium
RT chrysogenum.";
RL EMBO J. 10:489-495(1991).
RN [6]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=8416970; DOI=10.1016/s0021-9258(18)54203-4;
RA Lendenfeld T., Ghali D., Wolschek M., Kubicek-Pranz E.M., Kubicek C.P.;
RT "Subcellular compartmentation of penicillin biosynthesis in Penicillium
RT chrysogenum. The amino acid precursors are derived from the vacuole.";
RL J. Biol. Chem. 268:665-671(1993).
RN [7]
RP INDUCTION.
RX PubMed=7614558; DOI=10.1007/bf00352104;
RA Feng B., Friedlin E., Marzluf G.A.;
RT "Nuclear DNA-binding proteins which recognize the intergenic control region
RT of penicillin biosynthetic genes.";
RL Curr. Genet. 27:351-358(1995).
RN [8]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=9266851; DOI=10.1006/bbrc.1997.7107;
RA Etchegaray A., Dieckmann R., Kennedy J., Turner G., von Doehren H.;
RT "ACV synthetase: expression of amino acid activating domains of the
RT Penicillium chrysogenum enzyme in Aspergillus nidulans.";
RL Biochem. Biophys. Res. Commun. 237:166-169(1997).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR, AND
RP PATHWAY.
RX PubMed=9355751; DOI=10.1042/bj3270185;
RA Theilgaard H.B., Kristiansen K.N., Henriksen C.M., Nielsen J.;
RT "Purification and characterization of delta-(L-alpha-aminoadipyl)-L-
RT cysteinyl-D-valine synthetase from Penicillium chrysogenum.";
RL Biochem. J. 327:185-191(1997).
RN [10]
RP INDUCTION.
RX PubMed=10644695; DOI=10.1074/jbc.275.4.2423;
RA Kosalkova K., Marcos A.T., Fierro F., Hernando-Rico V., Gutierrez S.,
RA Martin J.F.;
RT "A novel heptameric sequence (TTAGTAA) is the binding site for a protein
RT required for high level expression of pcbAB, the first gene of the
RT penicillin biosynthesis in Penicillium chrysogenum.";
RL J. Biol. Chem. 275:2423-2430(2000).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=12223189; DOI=10.1016/s1087-1845(02)00036-1;
RA van der Lende T.R., van de Kamp M., Berg M., Sjollema K., Bovenberg R.A.,
RA Veenhuis M., Konings W.N., Driessen A.J.;
RT "delta-(L-alpha-Aminoadipyl)-L-cysteinyl-D-valine synthetase, that mediates
RT the first committed step in penicillin biosynthesis, is a cytosolic
RT enzyme.";
RL Fungal Genet. Biol. 37:49-55(2002).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=19686863; DOI=10.1016/j.ymben.2009.08.002;
RA Siewers V., Chen X., Huang L., Zhang J., Nielsen J.;
RT "Heterologous production of non-ribosomal peptide LLD-ACV in Saccharomyces
RT cerevisiae.";
RL Metab. Eng. 11:391-397(2009).
RN [13]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, MUTAGENESIS OF 3339-GLU--GLU-3344 AND
RP SER-3599, AND PATHWAY.
RX PubMed=21889568; DOI=10.1016/j.biochi.2011.08.002;
RA Wu X., Garcia-Estrada C., Vaca I., Martin J.F.;
RT "Motifs in the C-terminal region of the Penicillium chrysogenum ACV
RT synthetase are essential for valine epimerization and processivity of
RT tripeptide formation.";
RL Biochimie 94:354-364(2012).
RN [14]
RP INDUCTION.
RX PubMed=22960281; DOI=10.1016/j.fgb.2012.08.002;
RA Dominguez-Santos R., Martin J.F., Kosalkova K., Prieto C., Ullan R.V.,
RA Garcia-Estrada C.;
RT "The regulatory factor PcRFX1 controls the expression of the three genes of
RT beta-lactam biosynthesis in Penicillium chrysogenum.";
RL Fungal Genet. Biol. 49:866-881(2012).
RN [15]
RP FUNCTION.
RX PubMed=22777282; DOI=10.1007/s00253-012-4256-0;
RA Fernandez-Aguado M., Teijeira F., Martin J.F., Ullan R.V.;
RT "A vacuolar membrane protein affects drastically the biosynthesis of the
RT ACV tripeptide and the beta-lactam pathway of Penicillium chrysogenum.";
RL Appl. Microbiol. Biotechnol. 97:795-808(2013).
RN [16]
RP FUNCTION.
RX PubMed=24480587; DOI=10.1016/j.ymben.2014.01.004;
RA Fernandez-Aguado M., Martin J.F., Rodriguez-Castro R., Garcia-Estrada C.,
RA Albillos S.M., Teijeira F., Ullan R.V.;
RT "New insights into the isopenicillin N transport in Penicillium
RT chrysogenum.";
RL Metab. Eng. 22:89-103(2014).
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:1368505, PubMed:9266851, PubMed:21889568).
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:9266851, PubMed:9355751, PubMed:19686863,
CC PubMed:21889568). The precursor amino acids for penicillin biosynthesis
CC are withdrawn from the vacuolar amino acid pool by the MFS-type
CC transporter penV (PubMed:8416970, PubMed:22777282). Each of the
CC constituent amino acids of the tripeptide ACV are activated as
CC aminoacyl-adenylates with peptide bonds formed through the
CC participation of amino acid thioester intermediates (PubMed:9266851,
CC PubMed:21889568). The penicillin biosynthesis occurs via 3 enzymatic
CC steps, the first corresponding to the production of the tripeptide N-
CC [(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV)
CC by the NRPS acvA. The tripeptide ACV is then cyclized to isopenicillin
CC N (IPN) by the isopenicillin N synthase ipnA that forms the beta-lactam
CC nucleus. Finally, the alpha-aminoadipyl side chain is exchanged for
CC phenylacetic acid by the isopenicillin N acyltransferase aatA to yield
CC penicillin in the peroxisomal matrix (PubMed:1368505) (Probable).
CC {ECO:0000269|PubMed:1368505, ECO:0000269|PubMed:19686863,
CC ECO:0000269|PubMed:21889568, ECO:0000269|PubMed:22777282,
CC ECO:0000269|PubMed:8416970, ECO:0000269|PubMed:9266851,
CC ECO:0000269|PubMed:9355751, ECO:0000305|PubMed:1368505}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3 ATP + H2O + L-2-aminoadipate + L-cysteine + L-valine = 3 AMP
CC + 3 diphosphate + 3 H(+) + N-[(5S)-5-amino-5-carboxypentanoyl]-L-
CC cysteinyl-D-valine; 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:1368505, ECO:0000269|PubMed:19686863,
CC ECO:0000269|PubMed:21889568, ECO:0000269|PubMed:9266851,
CC ECO:0000269|PubMed:9355751};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23197;
CC Evidence={ECO:0000269|PubMed:1368505, ECO:0000269|PubMed:19686863,
CC ECO:0000269|PubMed:21889568, ECO:0000269|PubMed:9266851,
CC ECO:0000269|PubMed:9355751};
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:0000269|PubMed:9355751};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=46 uM for L-2-aminoadipate {ECO:0000269|PubMed:9355751};
CC KM=80 uM for L-cysteine {ECO:0000269|PubMed:9355751};
CC KM=83 uM for L-valine {ECO:0000269|PubMed:9355751};
CC pH dependence:
CC Optimum pH is 8.4. {ECO:0000269|PubMed:9355751};
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:1368505, ECO:0000269|PubMed:19686863,
CC ECO:0000269|PubMed:21889568, ECO:0000269|PubMed:9266851,
CC ECO:0000269|PubMed:9355751}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:12223189}.
CC Vacuole membrane {ECO:0000269|PubMed:1899377,
CC ECO:0000269|PubMed:8416970}; Peripheral membrane protein
CC {ECO:0000269|PubMed:8416970}. Note=Loosely attached to the vacuoles.
CC {ECO:0000269|PubMed:8416970}.
CC -!- INDUCTION: Expression is repressed by glucose (PubMed:3096965). The
CC transcription factor rfx1 controls penicillin biosynthesis through the
CC regulation of the acvA, ipnA and aatA transcription (PubMed:22960281).
CC The promoter heptameric sequence 5'-TTAGTAA-3' is the binding site for
CC the transcriptional activator named penicillin transcriptional
CC activator 1 (PTA1) (PubMed:10644695). Multiple additional DNA-binding
CC proteins appear to bind to the promoter, including the nuclear factor A
CC (NF-A) that recognizes an the 5'-GCCAAGCC-3' sequence or the global-
CC acting nitrogen regulatory protein NIT2 that binds strongly at a single
CC site that contains two closely spaced GATA sequences (PubMed:7614558).
CC {ECO:0000269|PubMed:10644695, ECO:0000269|PubMed:22960281,
CC ECO:0000269|PubMed:3096965, ECO:0000269|PubMed:7614558}.
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:0000269|PubMed:21889568,
CC ECO:0000269|PubMed:9266851}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA63415.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; M57425; AAA63415.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X54296; CAA38195.1; -; Genomic_DNA.
DR PIR; A37886; YGPLV8.
DR PIR; S13134; YGPLV3.
DR SMR; P19787; -.
DR ESTHER; pench-acvt; Thioesterase.
DR BioCyc; MetaCyc:MON-13331; -.
DR UniPathway; UPA00149; UER00239.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005774; C:vacuolar membrane; IDA:UniProtKB.
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:UniProtKB.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0042318; P:penicillin biosynthetic process; IDA:UniProtKB.
DR Gene3D; 1.10.1200.10; -; 3.
DR Gene3D; 3.30.300.30; -; 3.
DR Gene3D; 3.30.559.10; -; 3.
DR Gene3D; 3.40.50.12780; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR029058; AB_hydrolase.
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.
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 InterPro; IPR001031; Thioesterase.
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; SSF47336; SSF47336; 3.
DR SUPFAM; SSF53474; SSF53474; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 3.
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; Ligase; Magnesium;
KW Membrane; Multifunctional enzyme; Nucleotide-binding; Phosphopantetheine;
KW Phosphoprotein; Repeat; Vacuole.
FT CHAIN 1..3746
FT /note="N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine
FT synthase"
FT /id="PRO_0000193060"
FT DOMAIN 818..895
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 1902..1979
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 2991..3066
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 299..711
FT /note="Adenylation (A) domain 1"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:9266851"
FT REGION 918..1372
FT /note="Condensation (C) domain 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:21889568"
FT REGION 1391..1801
FT /note="Adenylation (A) domain 2"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:9266851"
FT REGION 1994..2434
FT /note="Condensation (C) domain 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:21889568"
FT REGION 2478..2883
FT /note="Adenylation (A) domain 3"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:9266851"
FT REGION 3084..3500
FT /note="Epimerase (E) domain"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:21889568"
FT REGION 3530..3732
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:21889568"
FT MOD_RES 855
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1939
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3026
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 3339..3344
FT /note="EGHGRE->LGFGLL: Impairs epimerase activity and
FT blocks tripeptide ACV production."
FT /evidence="ECO:0000269|PubMed:21889568"
FT MUTAGEN 3599
FT /note="S->A: Impairs tripeptide ACV production."
FT /evidence="ECO:0000269|PubMed:21889568"
SQ SEQUENCE 3746 AA; 421076 MW; 449BCC73253ED589 CRC64;
MGPSNPAMAY FKPSTRDTMD PCSGNAADGS IRVRFRGGIE RWKECVNQVP ERCDLSGLTT
DSTRYQLAST GFGDASAAYQ ERLMTVPVDV HAALQELCLE RRVSVGSVIN FSVHQMLKGF
GNGTHTITAS LHREQNLQNS SPSWVVSPTI VTHENRDGWS VAQAVESIEA GRGSEKESVT
AIDSGSSLVK MGLFDLLVSF VDADDARIPC FDFPLAVIVR ECDANLSLTL RFSDCLFNEE
TICNFTDALN ILLAEAVIGR VTPVADIELL SAEQKQQLEE WNNTDGEYPS SKRLHHLIEE
VVERHEDKIA VVCDERELTY GELNAQGNSL ARYLRSIGIL PEQLVALFLD KSEKLIVTIL
GVWKSGAAYV PIDPTYPDER VRFVLDDTKA RAIIASNQHV ERLQREVIGD RNLCIIRLEP
LLASLAQDSS KFPAHNLDDL PLTSQQLAYV TYTSGTTGFP KGIFKQHTNV VNSITDLSAR
YGVAGQHHEA ILLFSACVFE PFVRQTLMAL VNGHLLAVIN DVEKYDADTL LPFIRRHSIT
YLNGTASVLQ EYDFSDCPSL NRIILVGENL TEARYLALRQ RFKNRILNEY GFTESAFVTA
LKIFDPESTR KDTSLGRPVR NVKCYILNPS LKRVPIGATG ELHIGGLGIS KGYLNRPELT
PHRFIPNPFQ TDCEKQLGIN SLMYKTGDLA RWLPNGEVEY LGRADFQIKL RGIRIEPGEI
ETMLAMYPRV RTSLVVSKKL RNGPEETTNE HLVGYYVCDS ASVSEADLLS FLEKKLPRYM
IPTRLVQLSQ IPVNVNGKAD LRALPAVDIS NSTEVRSDLR GDTEIALGEI WADVLGARQR
SVSRNDNFFR LGGHSITCIQ LIARIRQRLS VSISVEDVFA TRTLERMADL LQNKQQEKCD
KPHEAPTELL EENAATDNIY LANSLQQGFV YHYLKSMEQS DAYVMQSVLR YNTTLSPDLF
QRAWKHAQQS FPALRLRFSW EKEVFQLLDQ DPPLDWRFLY FTDVAAGAVE DRKLEDLRRQ
DLTERFKLDV GRLFRVYLIK HSENRFTCLF SCHHAILDGW SLPLLFEKVH ETYLQLLHGD
NLTSSMDDPY TRTQRYLHAH REDHLDFWAG VVQKINERCD MNALLNERSR YKVQLADYDQ
VQEQRQLTIA LSGDAWLADL RQTCSAQGIT LHSILQFVWH AVLHAYGGGT HTITGTTISG
RNLPILGIER AVGPYINTLP LVLDHSTFKD KTIMEAIEDV QAKVNVMNSR GNVELGRLHK
TDLKHGLFDS LFVLENYPNL DKSRTLEHQT ELGYSIEGGT EKLNYPLAVI AREVETTGGF
TVSICYASEL FEEVMISELL HMVQDTLMQV ARGLNEPVGS LEYLSSIQLE QLAAWNATEA
EFPDTTLHEM FENEASQKPD KIAVVYEETS LTYRELNERA NRMAHQLRSD VSPNPNEVIA
LVMDKSEHMI VNILAVWKSG GAYVPIDPGY PNDRIQYILE DTQALAVIAD SCYLPRIKGM
AASGTLLYPS VLPANPDSKW SVSNPSPLSR STDLAYIIYT SGTTGRPKGV TVEHHGVVNL
QVSLSKVFGL RDTDDEVILS FSNYVFDHFV EQMTDAILNG QTLLVLNDGM RGDKERLYRY
IEKNRVTYLS GTPSVVSMYE FSRFKDHLRR VDCVGEAFSE PVFDKIRETF HGLVINGYGP
TEVSITTHKR LYPFPERRMD KSIGQQVHNS TSYVLNEDMK RTPIGSVGEL YLGGEGVVRG
YHNRADVTAE RFIPNPFQSE EDKREGRNSR LYKTGDLVRW IPGSSGEVEY LGRNDFQVKI
RGLRIELGEI EAILSSYHGI KQSVVIAKDC REGAQKFLVG YYVADAALPS AAIRRFMQSR
LPGYMVPSRL ILVSKFPVTP SGKLDTKALP PAEEESEIDV VPPRSEIERS LCDIWAELLE
MHPEEIGIYS DFFSLGGDSL KSTKLSFMIH ESFNRAVSVS ALFCHRTVEA QTHLILNDAA
DVHEITPIDC NDTQMIPVSR AQERLLFIHE FENGSNAYNI DAAFELPGSV DASLLEQALR
GNLARHEALR TLLVKDHATG IYLQKVLSPD EAQGMFSVNV DTAKQVERLD QEIASLSQHV
FRLDDELPWE ARILKLESGG LYLILAFHHT CFDAWSLKVF EQELRALYAA LQKTKSAANL
PALKAQYKEY ALYHRRQLSG DRMRNLSDFW LRKLIGLEPL QLITDRPRPV QFKYDGDDLS
IELSKKETEN LRGVAKRCKS SLYVVLVSVY CVMLASYANQ SDVSVGIPVS HRTHPQFQSV
IGFFVNLVVL RVDISQSAIC GLIRRVMKEL VDAQLHQDMP FQEVTKLLQV DNDPSRHPLV
QNVFNFESRA NGEHDARSED EGSLAFNQYR PVQPVDSVAK FDLNATVTEL ESGLRVNFNY
ATSLFNKSTI QGFLHTYEYL LRQLSELSAE GINEDTQLSL VRPTENGDLH LPLAQSPLAT
TAEEQKVASL NQAFEREAFL AAEKIAVVQG DRALSYADLN GQANQLARYI QSVSCIGADD
GIALMLEKSI DTIICILAIW KAGAAYVPLD PTYPPGRVQL ILEEIKAKAV LVHSSHASKC
ERHGAKVIAV DSPAIETAVS QQSAADLPTI ASLGNLAYII FTSGTSGKPK GVLVEQKAVL
LLRDALRERY FGRDCTKHHG VLFLSNYVFD FSVEQLVLSV LSGHKLIVPP AEFVADDEFY
RMASTHGLSY LSGTPSLLQK IDLARLDHLQ VVTAAGEELH ATQYEKMRRR FNGPIYNAYG
VTETTVYNII AEFTTNSIFE NALREVLPGT RAYVLNAALQ PVPFDAVGEL YLAGDSVTRG
YLNQPLLTDQ RFIPNPFCKE EDIAMGRFAR LYKTGDLVRS RFNRQQQPQL EYLGRGDLQI
KMRGYRIEIS EVQNVLTSSP GVREGAVVAK YENNDTYSRT AHSLVGYYTT DNETVSEADI
LTFMKARLPT YMVPSHLCCL EGALPVTING KLDVRRLPEI INDSAQSSYS PPRNIIEAKM
CRLWESALGM ERCGIDDDLF KLGGDSITSL HLVAQIHNQV GCKITVRDIF EHRTARALHD
HVFMKDSDRS NVTQFRTEQG PVIGEAPLLP IQDWFLSKAL QHPMYWNHTF YVRTPELDVD
SLSAAVRDLQ QYHDVFRMRL KREEVGFVQS FAEDFSPAQL RVLNVKDVDG SAAVNEILDG
WQSGFNLENG PIGSIGYLHG YEDRSARVWF SVHHMAIDTV SWQILVRDLQ TLYRNGSLGS
KGSSFRQWAE AIQNYKASDS ERNHWNKLVM ETASSISALP TSTGSRVRLS RSLSPEKTAS
LIQGGIDRQD VSVYDSLLTS VGLALQHIAP TGPSMVTIEG HGREEVDQTL DVSRTMGWFT
TMYPFEIPRL STENIVQGVV AVSERFRQVP ARGVGYGTLY GYTQHPLPQV TVNYLGQLAR
KQSKPKEWVL AVGDNEFEYG LMTSPEDKDR SSSAVDVTAV CIDGTMIIDV DSAWSLEESE
QFISSIEEGL NKILDGRASQ QTSRFPDVPQ PAETYTPYFE YLEPPRQGPT LFLLPPGEGG
AESYFNNIVK RLRQTNMVVF NNYYLHSKRL RTFEELAEMY LDQVRGIQPH GPYHFIGWSF
GGILAMEMSR RLVASDEKIG FLGIIDTYFN VRGATRTIGL GDTEILDPIH HIYNPDPANF
QRLPSATDRI VLFKAMRPNN KYESENQRRL YEYYDGTRLN GLDSLLPSDS DVQLVPLTDD
THFSWVGNPQ QVEQMCATIK EHLARY
