LOVF_ASPTN
ID LOVF_ASPTN Reviewed; 2452 AA.
AC Q0C8L6;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 110.
DE RecName: Full=Lovastatin diketide synthase lovF {ECO:0000303|PubMed:10334994};
DE Short=LDKS {ECO:0000303|PubMed:10334994};
DE EC=2.3.1.244 {ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:21069965};
DE AltName: Full=Lovastatin biosynthesis cluster protein F {ECO:0000303|PubMed:10334994};
GN Name=lovF {ECO:0000303|PubMed:10334994}; ORFNames=ATEG_09968;
OS Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=341663;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NIH 2624 / FGSC A1156;
RA Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA Nierman W.C., Milne T., Madden K.;
RT "Annotation of the Aspergillus terreus NIH2624 genome.";
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=6933445; DOI=10.1073/pnas.77.7.3957;
RA Alberts A.W., Chen J., Kuron G., Hunt V., Huff J., Hoffman C., Rothrock J.,
RA Lopez M., Joshua H., Harris E., Patchett A., Monaghan R., Currie S.,
RA Stapley E., Albers-Schonberg G., Hensens O., Hirshfield J., Hoogsteen K.,
RA Liesch J., Springer J.;
RT "Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-
RT coenzyme A reductase and a cholesterol-lowering agent.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:3957-3961(1980).
RN [3]
RP FUNCTION.
RX PubMed=10381407; DOI=10.1016/s1074-5521(99)80061-1;
RA Hendrickson L., Davis C.R., Roach C., Nguyen D.K., Aldrich T., McAda P.C.,
RA Reeves C.D.;
RT "Lovastatin biosynthesis in Aspergillus terreus: characterization of
RT blocked mutants, enzyme activities and a multifunctional polyketide
RT synthase gene.";
RL Chem. Biol. 6:429-439(1999).
RN [4]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=10334994; DOI=10.1126/science.284.5418.1368;
RA Kennedy J., Auclair K., Kendrew S.G., Park C., Vederas J.C.,
RA Hutchinson C.R.;
RT "Modulation of polyketide synthase activity by accessory proteins during
RT lovastatin biosynthesis.";
RL Science 284:1368-1372(1999).
RN [5]
RP FUNCTION.
RX PubMed=12929390; DOI=10.1039/b207721c;
RA Sorensen J.L., Auclair K., Kennedy J., Hutchinson C.R., Vederas J.C.;
RT "Transformations of cyclic nonaketides by Aspergillus terreus mutants
RT blocked for lovastatin biosynthesis at the lovA and lovC genes.";
RL Org. Biomol. Chem. 1:50-59(2003).
RN [6]
RP FUNCTION.
RX PubMed=17113998; DOI=10.1016/j.chembiol.2006.09.008;
RA Xie X., Watanabe K., Wojcicki W.A., Wang C.C., Tang Y.;
RT "Biosynthesis of lovastatin analogs with a broadly specific
RT acyltransferase.";
RL Chem. Biol. 13:1161-1169(2006).
RN [7]
RP FUNCTION.
RX PubMed=18988191; DOI=10.1002/bit.22028;
RA Xie X., Pashkov I., Gao X., Guerrero J.L., Yeates T.O., Tang Y.;
RT "Rational improvement of simvastatin synthase solubility in Escherichia
RT coli leads to higher whole-cell biocatalytic activity.";
RL Biotechnol. Bioeng. 102:20-28(2009).
RN [8]
RP FUNCTION.
RX PubMed=19875080; DOI=10.1016/j.chembiol.2009.09.017;
RA Gao X., Xie X., Pashkov I., Sawaya M.R., Laidman J., Zhang W., Cacho R.,
RA Yeates T.O., Tang Y.;
RT "Directed evolution and structural characterization of a simvastatin
RT synthase.";
RL Chem. Biol. 16:1064-1074(2009).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH LOVD, COFACTOR,
RP IDENTIFICATION BY MASS SPECTROMETRY, PATHWAY, BIOTECHNOLOGY, AND DOMAIN.
RX PubMed=19530726; DOI=10.1021/ja903203g;
RA Xie X., Meehan M.J., Xu W., Dorrestein P.C., Tang Y.;
RT "Acyltransferase mediated polyketide release from a fungal megasynthase.";
RL J. Am. Chem. Soc. 131:8388-8389(2009).
RN [10]
RP FUNCTION.
RX PubMed=19900898; DOI=10.1126/science.1175602;
RA Ma S.M., Li J.W., Choi J.W., Zhou H., Lee K.K., Moorthie V.A., Xie X.,
RA Kealey J.T., Da Silva N.A., Vederas J.C., Tang Y.;
RT "Complete reconstitution of a highly reducing iterative polyketide
RT synthase.";
RL Science 326:589-592(2009).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, COFACTOR, PHOSPHOPANTETHEINE AT
RP SER-2490, IDENTIFICATION BY MASS SPECTROMETRY, AND DOMAIN.
RX PubMed=21069965; DOI=10.1021/bi1014776;
RA Meehan M.J., Xie X., Zhao X., Xu W., Tang Y., Dorrestein P.C.;
RT "FT-ICR-MS characterization of intermediates in the biosynthesis of the
RT alpha-methylbutyrate side chain of lovastatin by the 277 kDa polyketide
RT synthase LovF.";
RL Biochemistry 50:287-299(2011).
RN [12]
RP FUNCTION.
RX PubMed=21495633; DOI=10.1021/ja201138v;
RA Barriuso J., Nguyen D.T., Li J.W., Roberts J.N., MacNevin G., Chaytor J.L.,
RA Marcus S.L., Vederas J.C., Ro D.K.;
RT "Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin
RT J by a single cytochrome P450 monooxygenase, LovA.";
RL J. Am. Chem. Soc. 133:8078-8081(2011).
RN [13]
RP FUNCTION.
RX PubMed=22733743; DOI=10.1073/pnas.1113029109;
RA Ames B.D., Nguyen C., Bruegger J., Smith P., Xu W., Ma S., Wong E.,
RA Wong S., Xie X., Li J.W., Vederas J.C., Tang Y., Tsai S.C.;
RT "Crystal structure and biochemical studies of the trans-acting polyketide
RT enoyl reductase LovC from lovastatin biosynthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11144-11149(2012).
RN [14]
RP FUNCTION.
RX PubMed=23653178; DOI=10.1002/anie.201302406;
RA Xu W., Chooi Y.H., Choi J.W., Li S., Vederas J.C., Da Silva N.A., Tang Y.;
RT "LovG: the thioesterase required for dihydromonacolin L release and
RT lovastatin nonaketide synthase turnover in lovastatin biosynthesis.";
RL Angew. Chem. Int. Ed. Engl. 52:6472-6475(2013).
RN [15]
RP FUNCTION.
RX PubMed=24727900; DOI=10.1038/nchembio.1503;
RA Jimenez-Oses G., Osuna S., Gao X., Sawaya M.R., Gilson L., Collier S.J.,
RA Huisman G.W., Yeates T.O., Tang Y., Houk K.N.;
RT "The role of distant mutations and allosteric regulation on LovD active
RT site dynamics.";
RL Nat. Chem. Biol. 10:431-436(2014).
RN [16]
RP BIOTECHNOLOGY.
RX PubMed=29236027; DOI=10.3390/ijms18122690;
RA Chen M.C., Tsai Y.C., Tseng J.H., Liou J.J., Horng S., Wen H.C., Fan Y.C.,
RA Zhong W.B., Hsu S.P.;
RT "Simvastatin inhibits cell proliferation and migration in human anaplastic
RT thyroid cancer.";
RL Int. J. Mol. Sci. 18:0-0(2017).
RN [17]
RP BIOTECHNOLOGY.
RX PubMed=29932104; DOI=10.3390/ijms19071834;
RA Zhong W.B., Tsai Y.C., Chin L.H., Tseng J.H., Tang L.W., Horng S.,
RA Fan Y.C., Hsu S.P.;
RT "A synergistic anti-cancer effect of troglitazone and lovastatin in a human
RT anaplastic thyroid cancer cell line and in a mouse xenograft model.";
RL Int. J. Mol. Sci. 19:0-0(2018).
CC -!- FUNCTION: Lovastatin diketide synthase; part of the gene cluster that
CC mediates the biosynthesis of lovastatin (also known as mevinolin,
CC mevacor or monacolin K), a hypolipidemic inhibitor of (3S)-
CC hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)
CC (PubMed:10334994, PubMed:12929390, PubMed:21495633). The first step in
CC the biosynthesis of lovastatin is the production of dihydromonacolin L
CC acid by the lovastatin nonaketide synthase lovB and the trans-acting
CC enoyl reductase lovC via condensation of one acetyl-CoA unit and 8
CC malonyl-CoA units (PubMed:10334994, PubMed:10381407, PubMed:19900898,
CC PubMed:22733743). Dihydromonacolin L acid is released from lovB by the
CC thioesterase lovG (PubMed:23653178). Next, dihydromonacolin L acid is
CC oxidized by the dihydromonacolin L monooxygenase lovA twice to form
CC monacolin J acid (PubMed:12929390, PubMed:21495633). The 2-
CC methylbutyrate moiety of lovastatin is synthesized by the lovastatin
CC diketide synthase lovF via condensation of one acetyl-CoA unit and one
CC malonyl-CoA unit (PubMed:19530726, PubMed:21069965). Finally, the
CC covalent attachment of this moiety to monacolin J acid is catalyzed by
CC the transesterase lovD to yield lovastatin (PubMed:10334994,
CC PubMed:17113998, PubMed:18988191, PubMed:19875080, PubMed:24727900).
CC LovD has broad substrate specificity and can also convert monacolin J
CC to simvastatin using alpha-dimethylbutanoyl-S-methyl-3-
CC mercaptopropionate (DMB-S-MMP) as the thioester acyl donor, and can
CC also catalyze the reverse reaction and function as hydrolase in vitro
CC (PubMed:19875080). LovD has much higher activity with LovF-bound 2-
CC methylbutanoate than with free diketide substrates (PubMed:21069965).
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407,
CC ECO:0000269|PubMed:12929390, ECO:0000269|PubMed:17113998,
CC ECO:0000269|PubMed:18988191, ECO:0000269|PubMed:19530726,
CC ECO:0000269|PubMed:19875080, ECO:0000269|PubMed:19900898,
CC ECO:0000269|PubMed:21069965, ECO:0000269|PubMed:21495633,
CC ECO:0000269|PubMed:22733743, ECO:0000269|PubMed:23653178,
CC ECO:0000269|PubMed:24727900}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3 H(+) + holo-[2-methylbutanoate polyketide synthase] + 2
CC malonyl-CoA + 2 NADPH + S-adenosyl-L-methionine = (S)-2-
CC methylbutanoyl-[2-methylbutanoate polyketide synthase] + 2 CO2 + 2
CC CoA + H2O + 2 NADP(+) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:42852, Rhea:RHEA-COMP:10260, Rhea:RHEA-COMP:10261,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:58349, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:64479, ChEBI:CHEBI:82764; EC=2.3.1.244;
CC Evidence={ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:21069965};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:21069965};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:21069965};
CC -!- PATHWAY: Polyketide biosynthesis; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:19530726,
CC ECO:0000269|PubMed:21069965}.
CC -!- SUBUNIT: Interacts with LovD. {ECO:0000269|PubMed:19530726}.
CC -!- DOMAIN: Multidomain protein; including a ketosynthase (KS) that
CC catalyzes repeated decarboxylative condensation to elongate the
CC polyketide backbone; a malonyl-CoA:ACP transacylase (MAT) that selects
CC and transfers the extender unit malonyl-CoA; a dehydratase (DH) domain
CC that reduces hydroxyl groups to enoyl groups; a methyltransferase
CC (CMeT) domain responsible for the incorporation of methyl groups; an
CC enoylreductase (ER) domain that reduces enoyl groups to alkyl group; a
CC ketoreductase (KR) domain that catalyzes beta-ketoreduction steps; and
CC an acyl-carrier protein (ACP) that serves as the tether of the growing
CC and completed polyketide via its phosphopantetheinyl arm.
CC {ECO:0000305|PubMed:19530726, ECO:0000305|PubMed:21069965}.
CC -!- DISRUPTION PHENOTYPE: Loss of lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994}.
CC -!- BIOTECHNOLOGY: Lovastatin acts as a hypolipidemic agent that works as
CC inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
CC (HMGR) which reduces HMG-CoA to mevalonate and is the key step in
CC cholesterol biosynthesis (PubMed:6933445). Lovastatin, simvastatin and
CC related compounds are widely used to treat hypercholesteremia and
CC reduce the risk of cardiovascular disease (PubMed:6933445).
CC Furthermore, statins such as lovastatin were found to be anticancer
CC agents (PubMed:29236027, PubMed:29932104).
CC {ECO:0000269|PubMed:29236027, ECO:0000269|PubMed:29932104,
CC ECO:0000269|PubMed:6933445}.
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DR EMBL; CH476609; EAU29417.1; -; Genomic_DNA.
DR RefSeq; XP_001209270.1; XM_001209270.1.
DR AlphaFoldDB; Q0C8L6; -.
DR SMR; Q0C8L6; -.
DR STRING; 341663.Q0C8L6; -.
DR EnsemblFungi; EAU29417; EAU29417; ATEG_09968.
DR GeneID; 4319643; -.
DR VEuPathDB; FungiDB:ATEG_09968; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_31_0_1; -.
DR OMA; HAYESQH; -.
DR OrthoDB; 19161at2759; -.
DR UniPathway; UPA00875; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 2.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013149; ADH-like_C.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 2.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..2452
FT /note="Lovastatin diketide synthase lovF"
FT /id="PRO_0000449662"
FT DOMAIN 2373..2450
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 13..384
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT REGION 496..790
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT REGION 861..1166
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT REGION 997..1017
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1343..1528
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT REGION 1745..2064
FT /note="Enoylreductase (ER) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT REGION 2088..2260
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y7D5, ECO:0000255"
FT ACT_SITE 173
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 555
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 893
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2410
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2452 AA; 268120 MW; 4CB919463978E0D7 CRC64;
MTPLDAPGAP APIAVVGMGC RFGGGATDPQ KLWKLLEEGG SAWSKIPPSR FNVGGVYHPN
GQRVGSCMDP QYRLILEVVY EALEAGMYYI PWFHTWVLTL HGSAAGIPLE QVSGSKTGVF
AGTMYHDYQG SFQRQPEALP RYFITGNAGT MLANRVSHFY DLRGPSVSID TACSTTLTAL
HLAIQSLRAG ESDMAIVAGA NLLLNPDVFT TMSNLGFLSP DGISYSFDSR ADGYGRGEGV
AAIVLKTLPH AVRDGDPIRL IVRETAINQD GRTLAISTPS GEAQERLIRD CYQKARLDPK
QTSYVEAHGT GTGAGDPLEL GVISAAFPRQ QIQVGSVKAN IGHTEAIPLS SQSWIPTDGV
CRASINNFGF GGANAHAIVE RYAPFAETSM CSPNGYPGNY DGHVETDQAH IYVLSAKDEN
SCMRMVSRLC DYATHAREAD DWQLLANMAY TLGSRRSNFR WKAVCTAHNL TSLAQNLAGD
GMRPSKSAEQ VRLGWVFTGQ GAQWFAMGQE LSRPETESRV DQAEFSLPLS TALQIALVRL
LWSWNIQPVA VTSHSSGEAA AAYAIGALTA RSAIGISYIR GALTARDRLA SVHKGAMLAV
GLSRSEVGIY IRQVPLQSEE CLVVGCINSP SSVTVSGDLS AIAKLEELLH ADRIFARRLK
VTQAFHSSHM NSMTDAFRAG LTELFGADPS DAANANKDVI YASPRTGDRM HDFNSLRDPM
HWVECMLYPV EFESAFRQMC LDENDHMPKV DRIIEIGPHG ALGGPIKQIM QLPELAPCDI
PYLSCLSRGK SSLSTLRLLA SELIRAGFPV DLNAINFPRG CEAARVQVLS DLPPYPWNHE
TRYWKEPRIS QSARQRKGPV HDLIGLQEPL NLPLARSWHN VLRVSDLPWL RDHVVGSHIV
FPGAGFVCMA VIGISTLCSS DHESADFSYI LRDVNFAQAL ILPADGEEGI DLRLTICAPD
QSLGSQDWQR FLVHSITADK NDWTEHCTGL VRVDMDQPAS SLSNPQRADP RPWSRKTAPQ
DLWDSLHRVG IRHGPLFQNI TRIESDGRES WCTFAIADTA SAMPHAYESQ HIVHPTTLDS
AIQAAYTTLP FAGSRIKSAM VPARVGCMKI SSRLADLEAR DMLRAQAKMH SQSHCALVTD
VAVFDEADPF GGPVMELEGL VFQSLGASLG TSGRDSTDTG NTCSSWHWAP DISLVNPVWL
ERTLDTGIQK HEIGVILELR RCSVHFIQEA MESLSVGDVA RLSGHLAKFY AWMQAQLACA
QNGELGPESS SWTRDNEHAR CSLRSRVVAG STNGEMICRL GSVLPAILRR EVDPLEVMMD
GHLLSRYYVD ALKWSRSNAQ ASELVRLCCH KNPRARILEI GGGTGGCTQL VVDSLGPNPP
VGRYDFTDVS AGFFEAARKR FAGWQDVMDF RKLDIEDDPE AQGFVCGSYD VVLACQVLHA
TSNMQRTLTN VRKLLKPGGK LILVETTRDE LDLFFTFGLL PGWWLSEEPE RQSTPSLSPT
MWRSMLHATG FNGVEVEARD CDSDEFYMIS TMMSTAVQAT PTSCSDKLPE VLLVYVDSST
PMSWISDLQG AIRCRNCSVT SLQALRQVPP TEGQMCVFLG EMEHSMLGSV TNDDFTLLTS
MLQLAGGALW VTRGATMKSD DPLKALHLGL LRTMRNESHG KRFVSLDLDP SRNPWTGDSR
DAIVSVLDLV SMSDEKEFDY AERGGVIHVP RAFSDSINGG EEDGYALEPF QDSQHLLRLD
IRTPGLLDSL YFRKRSVDPY EPDKLPDDWV EIEPRAFGLN FRDIMVAMGQ LESNVMGFEC
AGVVTSLSET ARTIAPGLAV GDRVCALMNG HWASRVTTSR TNVVRIPETL SFPHAASIPL
AFTTAYISLY TVARILPGET VLIHAGAGGV GQAAIILAQL TGAEVFTTAG SEAKRNHLID
KFHLDPDHVF SSRDSSFVDG IKTRTSGKGV DVVLNSLAGP LLQKSFDCLA RFGRFVEIGK
KDLEQNSRLD MSTFVRNVSF SSVDILYWQQ AKSAEIFQAL SEVILLWGRT AIGLIHPISE
YPMSALEKAF RTMQSGQHVG KIVVTVAPDD AVLVRQERMP LFLKPNVSYL VAGGLGGIGR
RICEWLVDRG ARYLIILSRT ARVDPVVTSL QERGCTVSVQ ACDVADKSQL EAALQQCRAE
NLPPIRGVIQ GAMVLKDALV SQMTADGFHA ALRPKVQGSW NLHRIASDVD FFVMLSSLVG
VMGGAGQANY AAAGAFQDAL AEHRMAHNQP AVTIDLGMVQ SIGYVAETDS AVAERLQRIG
YQPLHEEEVL AVLEQAMSPV CSPTAPTRPA VIVTGINTRP GPHWAHADWM QEARFAGIKY
RDPLRDNNGA LPLTLAEDDN LHARLNRATS QQASIAVIME AMGRKLISMF GLTDSEMSAT
QTLAGIGVDS LVAIELRNWI TARFNVDISV FELMEGRTIA KVAEVVLQRY KP
