THYX_MYCTU
ID THYX_MYCTU Reviewed; 250 AA.
AC P9WG57; L0TD90; O33296; P66930;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 43.
DE RecName: Full=Flavin-dependent thymidylate synthase {ECO:0000303|PubMed:16139296, ECO:0000303|PubMed:16730023};
DE Short=FDTS {ECO:0000303|PubMed:21657202};
DE EC=2.1.1.148 {ECO:0000269|PubMed:18493582};
DE AltName: Full=FAD-dependent thymidylate synthase {ECO:0000303|PubMed:18192395};
DE AltName: Full=Thymidylate synthase ThyX {ECO:0000303|PubMed:18493582};
DE Short=TS {ECO:0000303|PubMed:18493582};
DE Short=TSase {ECO:0000255|HAMAP-Rule:MF_01408};
GN Name=thyX {ECO:0000303|PubMed:16139296}; OrderedLocusNames=Rv2754c;
GN ORFNames=MTV002.19c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=12657046; DOI=10.1046/j.1365-2958.2003.03425.x;
RA Sassetti C.M., Boyd D.H., Rubin E.J.;
RT "Genes required for mycobacterial growth defined by high density
RT mutagenesis.";
RL Mol. Microbiol. 48:77-84(2003).
RN [3]
RP IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [4]
RP MUTAGENESIS STUDY, AND SUBUNIT.
RC STRAIN=H37Rv;
RX PubMed=18192395; DOI=10.1128/jb.01094-07;
RA Ulmer J.E., Boum Y., Thouvenel C.D., Myllykallio H., Sibley C.H.;
RT "Functional analysis of the Mycobacterium tuberculosis FAD-dependent
RT thymidylate synthase, ThyX, reveals new amino acid residues contributing to
RT an extended ThyX motif.";
RL J. Bacteriol. 190:2056-2064(2008).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, AND SUBUNIT.
RX PubMed=18493582; DOI=10.1371/journal.pone.0002237;
RA Hunter J.H., Gujjar R., Pang C.K., Rathod P.K.;
RT "Kinetics and ligand-binding preferences of Mycobacterium tuberculosis
RT thymidylate synthases, ThyA and ThyX.";
RL PLoS ONE 3:E2237-E2237(2008).
RN [6]
RP ACTIVITY REGULATION.
RX PubMed=21657202; DOI=10.1021/jm2004688;
RA Koegler M., Vanderhoydonck B., De Jonghe S., Rozenski J., Van Belle K.,
RA Herman J., Louat T., Parchina A., Sibley C., Lescrinier E., Herdewijn P.;
RT "Synthesis and evaluation of 5-substituted 2'-deoxyuridine monophosphate
RT analogues as inhibitors of flavin-dependent thymidylate synthase in
RT Mycobacterium tuberculosis.";
RL J. Med. Chem. 54:4847-4862(2011).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [8]
RP INDUCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=H37Rv;
RX PubMed=22034487; DOI=10.1099/mic.0.053983-0;
RA Fivian-Hughes A.S., Houghton J., Davis E.O.;
RT "Mycobacterium tuberculosis thymidylate synthase gene thyX is essential and
RT potentially bifunctional, while thyA deletion confers resistance to p-
RT aminosalicylic acid.";
RL Microbiology 158:308-318(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.01 ANGSTROMS) OF DOUBLE MUTANT MET-65/MET-175 IN
RP COMPLEX WITH THE SUBSTRATE ANALOG 5-BROMO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE
RP AND FAD, FUNCTION, COFACTOR, SUBUNIT, AND MUTAGENESIS OF ILE-65; HIS-69;
RP ARG-95; SER-105; TYR-108; LYS-165; ARG-168 AND LEU-175.
RC STRAIN=H37Rv;
RX PubMed=16139296; DOI=10.1016/j.jmb.2005.07.071;
RA Sampathkumar P., Turley S., Ulmer J.E., Rhie H.G., Sibley C.H., Hol W.G.;
RT "Structure of the Mycobacterium tuberculosis flavin dependent thymidylate
RT synthase (MtbThyX) at 2.0A resolution.";
RL J. Mol. Biol. 352:1091-1104(2005).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF DOUBLE MUTANT MET-65/MET-175 IN
RP COMPLEX WITH NADP.
RC STRAIN=H37Rv;
RX PubMed=16730023; DOI=10.1016/j.jmb.2006.04.061;
RA Sampathkumar P., Turley S., Sibley C.H., Hol W.G.;
RT "NADP+ expels both the co-factor and a substrate analog from the
RT Mycobacterium tuberculosis ThyX active site: opportunities for anti-
RT bacterial drug design.";
RL J. Mol. Biol. 360:1-6(2006).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH FAD AND
RP 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE.
RX PubMed=25613812; DOI=10.1016/j.tube.2014.12.003;
RA Baugh L., Phan I., Begley D.W., Clifton M.C., Armour B., Dranow D.M.,
RA Taylor B.M., Muruthi M.M., Abendroth J., Fairman J.W., Fox D. III,
RA Dieterich S.H., Staker B.L., Gardberg A.S., Choi R., Hewitt S.N.,
RA Napuli A.J., Myers J., Barrett L.K., Zhang Y., Ferrell M., Mundt E.,
RA Thompkins K., Tran N., Lyons-Abbott S., Abramov A., Sekar A.,
RA Serbzhinskiy D., Lorimer D., Buchko G.W., Stacy R., Stewart L.J.,
RA Edwards T.E., Van Voorhis W.C., Myler P.J.;
RT "Increasing the structural coverage of tuberculosis drug targets.";
RL Tuberculosis 95:142-148(2015).
CC -!- FUNCTION: Catalyzes the reductive methylation of 2'-deoxyuridine-5'-
CC monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP) while
CC utilizing 5,10-methylenetetrahydrofolate (mTHF) as the methyl donor,
CC and NADPH and FADH(2) as the reductant (PubMed:18493582). Is essential
CC for growth of the pathogen on solid media in vitro; the essential
CC function is something other than dTMP synthase (PubMed:12657046)
CC (PubMed:22034487). {ECO:0000269|PubMed:12657046,
CC ECO:0000269|PubMed:16139296, ECO:0000269|PubMed:18493582,
CC ECO:0000269|PubMed:22034487}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + dUMP + H(+) +
CC NADPH = (6S)-5,6,7,8-tetrahydrofolate + dTMP + NADP(+);
CC Xref=Rhea:RHEA:29043, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:57453, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:63528, ChEBI:CHEBI:246422; EC=2.1.1.148;
CC Evidence={ECO:0000269|PubMed:18493582};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:16139296};
CC Note=Binds 4 FAD per tetramer. Each FAD binding site is formed by three
CC monomers. {ECO:0000269|PubMed:16139296};
CC -!- ACTIVITY REGULATION: Is potently inhibited by 5-fluoro-2'-deoxyuridine
CC 5'-monophosphate (FdUMP), but in contrast to ThyA, is not inhibited by
CC the folate-based 1843U89 (PubMed:18493582). A 5-alkynyl dUMP analog has
CC been shown to highly inhibit ThyX (IC(50) value of 0.91 uM), while
CC lacking activity against the classical mycobacterial thymidylate
CC synthase ThyA, and therefore is a selective mycobacterial FDTS
CC inhibitor (PubMed:21657202). {ECO:0000269|PubMed:18493582,
CC ECO:0000269|PubMed:21657202}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3 uM for dUMP {ECO:0000269|PubMed:18493582};
CC KM=4 uM for 5,10-methylenetetrahydrofolate
CC {ECO:0000269|PubMed:18493582};
CC KM=47 uM for NADPH {ECO:0000269|PubMed:18493582};
CC Note=kcat is 0.4 min(-1). {ECO:0000269|PubMed:18493582};
CC -!- PATHWAY: Pyrimidine metabolism; dTTP biosynthesis. {ECO:0000255|HAMAP-
CC Rule:MF_01408}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:16139296,
CC ECO:0000269|PubMed:18192395, ECO:0000269|PubMed:18493582}.
CC -!- INDUCTION: Is expressed under the exponential phase of growth, and
CC down-regulated upon starvation. Expression of thyX is significantly
CC increased within murine macrophages or under acid stress. Is expressed
CC at a lower level than thyA under all of the in vitro and in vivo growth
CC conditions tested. {ECO:0000269|PubMed:22034487}.
CC -!- DISRUPTION PHENOTYPE: Cells lacking this gene display impaired growth
CC (PubMed:12657046). Strains with a thyX deletion could not be obtained
CC (PubMed:22034487). {ECO:0000269|PubMed:12657046,
CC ECO:0000269|PubMed:22034487}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000305|PubMed:19099550}.
CC -!- MISCELLANEOUS: Crystallographic studies have shown that NADPH/NADP(+)
CC binding expels both FAD and dUMP from the active site, by competing for
CC the binding site (PubMed:16730023). However, the location of NADPH
CC binding might not be biologically relevant (PubMed:18192395).
CC {ECO:0000269|PubMed:16730023, ECO:0000305|PubMed:18192395}.
CC -!- SIMILARITY: Belongs to the thymidylate synthase ThyX family.
CC {ECO:0000255|HAMAP-Rule:MF_01408}.
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DR EMBL; AL123456; CCP45553.1; -; Genomic_DNA.
DR PIR; A70880; A70880.
DR RefSeq; NP_217270.1; NC_000962.3.
DR RefSeq; WP_003899465.1; NZ_NVQJ01000020.1.
DR PDB; 2AF6; X-ray; 2.01 A; A/B/C/D/E/F/G/H=1-250.
DR PDB; 2GQ2; X-ray; 2.10 A; A/B/C/D=1-250.
DR PDB; 3GWC; X-ray; 1.90 A; A/B/C/D/E/F/G/H=1-250.
DR PDB; 3HZG; X-ray; 2.45 A; A/B/C/D=1-250.
DR PDBsum; 2AF6; -.
DR PDBsum; 2GQ2; -.
DR PDBsum; 3GWC; -.
DR PDBsum; 3HZG; -.
DR AlphaFoldDB; P9WG57; -.
DR SMR; P9WG57; -.
DR STRING; 83332.Rv2754c; -.
DR BindingDB; P9WG57; -.
DR ChEMBL; CHEMBL1795161; -.
DR PaxDb; P9WG57; -.
DR DNASU; 887766; -.
DR GeneID; 887766; -.
DR KEGG; mtu:Rv2754c; -.
DR TubercuList; Rv2754c; -.
DR eggNOG; COG1351; Bacteria.
DR OMA; AKLGPRC; -.
DR PhylomeDB; P9WG57; -.
DR BioCyc; MetaCyc:G185E-7003-MON; -.
DR BRENDA; 2.1.1.148; 3445.
DR UniPathway; UPA00575; -.
DR PRO; PR:P9WG57; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:MTBBASE.
DR GO; GO:0070402; F:NADPH binding; IDA:MTBBASE.
DR GO; GO:0050797; F:thymidylate synthase (FAD) activity; IDA:MTBBASE.
DR GO; GO:0004799; F:thymidylate synthase activity; IDA:MTBBASE.
DR GO; GO:0006231; P:dTMP biosynthetic process; IBA:GO_Central.
DR GO; GO:0006235; P:dTTP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR Gene3D; 3.30.1360.170; -; 1.
DR HAMAP; MF_01408; ThyX; 1.
DR InterPro; IPR003669; Thymidylate_synthase_ThyX.
DR InterPro; IPR036098; Thymidylate_synthase_ThyX_sf.
DR PANTHER; PTHR34934; PTHR34934; 1.
DR Pfam; PF02511; Thy1; 1.
DR SUPFAM; SSF69796; SSF69796; 1.
DR TIGRFAMs; TIGR02170; thyX; 1.
DR PROSITE; PS51331; THYX; 1.
PE 1: Evidence at protein level;
KW 3D-structure; FAD; Flavoprotein; Methyltransferase; NADP;
KW Nucleotide biosynthesis; Reference proteome; Transferase.
FT CHAIN 1..250
FT /note="Flavin-dependent thymidylate synthase"
FT /id="PRO_0000175570"
FT DOMAIN 7..233
FT /note="ThyX"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00661"
FT MOTIF 95..105
FT /note="ThyX motif"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01408"
FT ACT_SITE 199
FT /note="Involved in ionization of N3 of dUMP, leading to its
FT activation"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01408"
FT BINDING 71
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /ligand_note="ligand shared between neighboring subunits"
FT /evidence="ECO:0000269|PubMed:16139296,
FT ECO:0007744|PDB:2AF6, ECO:0007744|PDB:3GWC,
FT ECO:0007744|PDB:3HZG"
FT BINDING 87
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000305|PubMed:16139296,
FT ECO:0007744|PDB:2AF6"
FT BINDING 92..95
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000305|PubMed:16139296,
FT ECO:0007744|PDB:2AF6"
FT BINDING 95..97
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /ligand_note="ligand shared between neighboring subunits"
FT /evidence="ECO:0000269|PubMed:16139296,
FT ECO:0007744|PDB:2AF6, ECO:0007744|PDB:3GWC,
FT ECO:0007744|PDB:3HZG"
FT BINDING 103..107
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000305|PubMed:16139296,
FT ECO:0007744|PDB:2AF6"
FT BINDING 103
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /ligand_note="ligand shared between neighboring subunits"
FT /evidence="ECO:0000269|PubMed:16139296,
FT ECO:0007744|PDB:2AF6, ECO:0007744|PDB:3GWC,
FT ECO:0007744|PDB:3HZG"
FT BINDING 172
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000305|PubMed:16139296,
FT ECO:0007744|PDB:2AF6"
FT BINDING 188..190
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /ligand_note="ligand shared between neighboring subunits"
FT /evidence="ECO:0000269|PubMed:16139296,
FT ECO:0007744|PDB:2AF6, ECO:0007744|PDB:3GWC,
FT ECO:0007744|PDB:3HZG"
FT BINDING 194
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /ligand_note="ligand shared between neighboring subunits"
FT /evidence="ECO:0000269|PubMed:16139296,
FT ECO:0007744|PDB:2AF6, ECO:0007744|PDB:3GWC,
FT ECO:0007744|PDB:3HZG"
FT BINDING 199
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000305|PubMed:16139296,
FT ECO:0007744|PDB:2AF6"
FT MUTAGEN 65
FT /note="I->M: Still able to complement an E.coli thyA
FT deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 69
FT /note="H->E: Loss of catalytic activity since it is not
FT able to complement an E.coli thyA deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 95
FT /note="R->A,D: Loss of catalytic activity since it is not
FT able to complement an E.coli thyA deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 95
FT /note="R->K: Still able to complement an E.coli thyA
FT deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 105
FT /note="S->E: Loss of catalytic activity since it is not
FT able to complement an E.coli thyA deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 108
FT /note="Y->F: Still able to complement an E.coli thyA
FT deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 165
FT /note="K->A: Loss of catalytic activity since it is not
FT able to complement an E.coli thyA deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 168
FT /note="R->A: Loss of catalytic activity since it is not
FT able to complement an E.coli thyA deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT MUTAGEN 175
FT /note="L->M: Still able to complement an E.coli thyA
FT deletion mutant."
FT /evidence="ECO:0000269|PubMed:16139296"
FT STRAND 8..17
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 31..44
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 52..54
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 57..66
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 70..75
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 77..86
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 87..93
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 99..103
FT /evidence="ECO:0007829|PDB:3GWC"
FT TURN 106..108
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 111..113
FT /evidence="ECO:0007829|PDB:2GQ2"
FT HELIX 120..122
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 126..154
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 160..171
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 172..174
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 179..188
FT /evidence="ECO:0007829|PDB:3GWC"
FT HELIX 189..199
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:3HZG"
FT HELIX 206..222
FT /evidence="ECO:0007829|PDB:3GWC"
FT TURN 224..226
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 231..234
FT /evidence="ECO:0007829|PDB:3GWC"
FT STRAND 240..243
FT /evidence="ECO:0007829|PDB:3GWC"
SQ SEQUENCE 250 AA; 27591 MW; 7BACFA59B5DA7294 CRC64;
MAETAPLRVQ LIAKTDFLAP PDVPWTTDAD GGPALVEFAG RACYQSWSKP NPKTATNAGY
LRHIIDVGHF SVLEHASVSF YITGISRSCT HELIRHRHFS YSQLSQRYVP EKDSRVVVPP
GMEDDADLRH ILTEAADAAR ATYSELLAKL EAKFADQPNA ILRRKQARQA ARAVLPNATE
TRIVVTGNYR AWRHFIAMRA SEHADVEIRR LAIECLRQLA AVAPAVFADF EVTTLADGTE
VATSPLATEA
