ID TYSY_LACCA Reviewed; 316 AA.
AC P00469;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 24-JAN-2024, entry version 147.
DE RecName: Full=Thymidylate synthase {ECO:0000255|HAMAP-Rule:MF_00008};
DE Short=TS {ECO:0000255|HAMAP-Rule:MF_00008};
DE Short=TSase {ECO:0000255|HAMAP-Rule:MF_00008};
DE EC=2.1.1.45 {ECO:0000255|HAMAP-Rule:MF_00008};
GN Name=thyA {ECO:0000255|HAMAP-Rule:MF_00008};
OS Lacticaseibacillus casei (Lactobacillus casei).
OC Bacteria; Bacillota; Bacilli; Lactobacillales; Lactobacillaceae;
OC Lacticaseibacillus.
OX NCBI_TaxID=1582;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2840247; DOI=10.1089/dna.1988.7.235;
RA Pinter K., Davisson V.J., Santi D.V.;
RT "Cloning, sequencing, and expression of the Lactobacillus casei thymidylate
RT synthase gene.";
RL DNA 7:235-241(1988).
RN [2]
RP PROTEIN SEQUENCE.
RX PubMed=105005; DOI=10.1016/s0021-9258(17)34202-3;
RA Maley G.F., Bellisario R.L., Guarino D.U., Maley F.;
RT "The primary structure of Lactobacillus casei thymidylate synthetase. III.
RT The use of 2-(2-nitrophenylsulfenyl)-3-methyl-3-bromoindolenine and limited
RT tryptic peptides to establish the complete amino acid sequence of the
RT enzyme.";
RL J. Biol. Chem. 254:1301-1304(1979).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS).
RX PubMed=2128651; DOI=10.1002/prot.340080406;
RA Perry K.M., Fauman E.B., Finer-Moore J.S., Montfort W.R., Maley G.F.,
RA Maley F., Stroud R.M.;
RT "Plastic adaptation toward mutations in proteins: structural comparison of
RT thymidylate synthases.";
RL Proteins 8:315-333(1990).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS).
RX PubMed=8371269; DOI=10.1006/jmbi.1993.1463;
RA Finer-Moore J.S., Fauman E.B., Foster P.G., Perry K.M., Santi D.V.,
RA Stroud R.M.;
RT "Refined structures of substrate-bound and phosphate-bound thymidylate
RT synthase from Lactobacillus casei.";
RL J. Mol. Biol. 232:1101-1116(1993).
RN [5]
RP MUTAGENESIS OF TYR-82.
RX PubMed=9383465; DOI=10.1016/1074-5521(95)90125-6;
RA Kealey J.T., Eckstein J., Santi D.V.;
RT "Role of the conserved tryptophan 82 of Lactobacillus casei thymidylate
RT synthase.";
RL Chem. Biol. 2:609-614(1995).
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 and
CC reductant in the reaction, yielding dihydrofolate (DHF) as a by-
CC product. This enzymatic reaction provides an intracellular de novo
CC source of dTMP, an essential precursor for DNA biosynthesis.
CC {ECO:0000255|HAMAP-Rule:MF_00008}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + dUMP = 7,8-
CC dihydrofolate + dTMP; Xref=Rhea:RHEA:12104, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:57451, ChEBI:CHEBI:63528, ChEBI:CHEBI:246422;
CC EC=2.1.1.45; Evidence={ECO:0000255|HAMAP-Rule:MF_00008};
CC -!- PATHWAY: Pyrimidine metabolism; dTTP biosynthesis. {ECO:0000255|HAMAP-
CC Rule:MF_00008}.
CC -!- SUBUNIT: Homodimer. {ECO:0000255|HAMAP-Rule:MF_00008}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_00008}.
CC -!- SIMILARITY: Belongs to the thymidylate synthase family. Bacterial-type
CC ThyA subfamily. {ECO:0000255|HAMAP-Rule:MF_00008}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA25255.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; M19653; AAA25255.1; ALT_INIT; Genomic_DNA.
DR PIR; A29817; SYLBT.
DR PDB; 1BO7; X-ray; 2.40 A; A=1-316.
DR PDB; 1BO8; X-ray; 2.40 A; A=1-316.
DR PDB; 1BP0; X-ray; 2.40 A; A=1-316.
DR PDB; 1BP6; X-ray; 2.40 A; A=1-316.
DR PDB; 1BPJ; X-ray; 2.40 A; A=1-316.
DR PDB; 1JMF; X-ray; 2.50 A; A=1-316.
DR PDB; 1JMG; X-ray; 2.20 A; A=1-316.
DR PDB; 1JMH; X-ray; 2.50 A; A=1-316.
DR PDB; 1JMI; X-ray; 2.50 A; A=1-316.
DR PDB; 1LCA; X-ray; 2.50 A; A=1-316.
DR PDB; 1LCB; X-ray; 2.50 A; A=1-316.
DR PDB; 1LCE; X-ray; 2.50 A; A=1-316.
DR PDB; 1NJA; X-ray; 2.50 A; A=1-316.
DR PDB; 1NJB; X-ray; 2.74 A; A=1-316.
DR PDB; 1NJC; X-ray; 2.50 A; A=1-316.
DR PDB; 1NJD; X-ray; 2.20 A; A=1-316.
DR PDB; 1NJE; X-ray; 2.30 A; A=1-316.
DR PDB; 1TDA; X-ray; 3.09 A; A=1-315.
DR PDB; 1TDB; X-ray; 2.65 A; A=1-315.
DR PDB; 1TDC; X-ray; 2.65 A; A=1-315.
DR PDB; 1THY; X-ray; 2.90 A; A=1-316.
DR PDB; 1TSL; X-ray; 2.50 A; A=1-316.
DR PDB; 1TSM; X-ray; 3.00 A; A=1-316.
DR PDB; 1TSV; X-ray; 2.90 A; A=1-316.
DR PDB; 1TSW; X-ray; 2.50 A; A=1-316.
DR PDB; 1TSX; X-ray; 2.50 A; A=1-316.
DR PDB; 1TSY; X-ray; 2.20 A; A=1-316.
DR PDB; 1TSZ; X-ray; 2.75 A; A=1-316.
DR PDB; 1TVU; X-ray; 2.50 A; A=1-316.
DR PDB; 1TVV; X-ray; 2.30 A; A=1-316.
DR PDB; 1TVW; X-ray; 2.50 A; A=1-316.
DR PDB; 1VZA; X-ray; 2.50 A; A=1-316.
DR PDB; 1VZB; X-ray; 2.50 A; A=1-316.
DR PDB; 1VZC; X-ray; 2.50 A; A=1-316.
DR PDB; 1VZD; X-ray; 2.50 A; A=1-316.
DR PDB; 1VZE; X-ray; 2.30 A; A=1-316.
DR PDB; 2G86; X-ray; 2.40 A; A=1-316.
DR PDB; 2G89; X-ray; 2.50 A; A=1-316.
DR PDB; 2G8A; X-ray; 2.40 A; A=1-316.
DR PDB; 2G8D; X-ray; 2.40 A; A=1-316.
DR PDB; 2TDD; X-ray; 2.70 A; A=1-315.
DR PDB; 2TDM; X-ray; 2.55 A; A=1-316.
DR PDB; 3BNZ; X-ray; 2.60 A; A=1-316.
DR PDB; 3BYX; X-ray; 2.40 A; A=1-316.
DR PDB; 3BZ0; X-ray; 2.70 A; A=1-316.
DR PDB; 3C06; X-ray; 2.60 A; A=1-316.
DR PDB; 3C0A; X-ray; 2.40 A; A=1-316.
DR PDB; 3IJZ; X-ray; 2.21 A; A=1-316.
DR PDB; 3IK0; X-ray; 2.10 A; A=1-316.
DR PDB; 3IK1; X-ray; 2.25 A; A=1-316.
DR PDB; 4TMS; X-ray; 2.35 A; A=1-316.
DR PDBsum; 1BO7; -.
DR PDBsum; 1BO8; -.
DR PDBsum; 1BP0; -.
DR PDBsum; 1BP6; -.
DR PDBsum; 1BPJ; -.
DR PDBsum; 1JMF; -.
DR PDBsum; 1JMG; -.
DR PDBsum; 1JMH; -.
DR PDBsum; 1JMI; -.
DR PDBsum; 1LCA; -.
DR PDBsum; 1LCB; -.
DR PDBsum; 1LCE; -.
DR PDBsum; 1NJA; -.
DR PDBsum; 1NJB; -.
DR PDBsum; 1NJC; -.
DR PDBsum; 1NJD; -.
DR PDBsum; 1NJE; -.
DR PDBsum; 1TDA; -.
DR PDBsum; 1TDB; -.
DR PDBsum; 1TDC; -.
DR PDBsum; 1THY; -.
DR PDBsum; 1TSL; -.
DR PDBsum; 1TSM; -.
DR PDBsum; 1TSV; -.
DR PDBsum; 1TSW; -.
DR PDBsum; 1TSX; -.
DR PDBsum; 1TSY; -.
DR PDBsum; 1TSZ; -.
DR PDBsum; 1TVU; -.
DR PDBsum; 1TVV; -.
DR PDBsum; 1TVW; -.
DR PDBsum; 1VZA; -.
DR PDBsum; 1VZB; -.
DR PDBsum; 1VZC; -.
DR PDBsum; 1VZD; -.
DR PDBsum; 1VZE; -.
DR PDBsum; 2G86; -.
DR PDBsum; 2G89; -.
DR PDBsum; 2G8A; -.
DR PDBsum; 2G8D; -.
DR PDBsum; 2TDD; -.
DR PDBsum; 2TDM; -.
DR PDBsum; 3BNZ; -.
DR PDBsum; 3BYX; -.
DR PDBsum; 3BZ0; -.
DR PDBsum; 3C06; -.
DR PDBsum; 3C0A; -.
DR PDBsum; 3IJZ; -.
DR PDBsum; 3IK0; -.
DR PDBsum; 3IK1; -.
DR PDBsum; 4TMS; -.
DR AlphaFoldDB; P00469; -.
DR SMR; P00469; -.
DR STRING; 1582.AAW28_04545; -.
DR BindingDB; P00469; -.
DR ChEMBL; CHEMBL5328; -.
DR DrugBank; DB03541; 10-Propargyl-5,8-Dideazafolic Acid.
DR DrugBank; DB03798; 2'-Deoxycytidine-5'-Monophosphate.
DR DrugBank; DB06860; 2-(2-chloropyridin-4-yl)-4-methyl-1H-isoindole-1,3(2H)-dione.
DR DrugBank; DB07507; 2-(4-hydroxybiphenyl-3-yl)-4-methyl-1H-isoindole-1,3(2H)-dione.
DR DrugBank; DB08204; 3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE.
DR DrugBank; DB07511; 4-(4-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile.
DR DrugBank; DB02301; 5,10-Methylene-6-Hydrofolic Acid.
DR DrugBank; DB03761; 5-fluoro-2'-deoxyuridine-5'-monophosphate.
DR DrugBank; DB03800; Deoxyuridine monophosphate.
DR DrugBank; DB01643; Thymidine monophosphate.
DR DrugBank; DB03685; Uridine monophosphate.
DR DrugCentral; P00469; -.
DR eggNOG; COG0207; Bacteria.
DR SABIO-RK; P00469; -.
DR UniPathway; UPA00575; -.
DR EvolutionaryTrace; P00469; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0004799; F:thymidylate synthase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0006231; P:dTMP biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0006235; P:dTTP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR CDD; cd00351; TS_Pyrimidine_HMase; 1.
DR Gene3D; 3.30.572.10; Thymidylate synthase/dCMP hydroxymethylase domain; 1.
DR HAMAP; MF_00008; Thymidy_synth_bact; 1.
DR InterPro; IPR045097; Thymidate_synth/dCMP_Mease.
DR InterPro; IPR023451; Thymidate_synth/dCMP_Mease_dom.
DR InterPro; IPR036926; Thymidate_synth/dCMP_Mease_sf.
DR InterPro; IPR000398; Thymidylate_synthase.
DR InterPro; IPR020940; Thymidylate_synthase_AS.
DR NCBIfam; TIGR03284; thym_sym; 1.
DR PANTHER; PTHR11548:SF9; THYMIDYLATE SYNTHASE; 1.
DR PANTHER; PTHR11548; THYMIDYLATE SYNTHASE 1; 1.
DR Pfam; PF00303; Thymidylat_synt; 1.
DR PRINTS; PR00108; THYMDSNTHASE.
DR SUPFAM; SSF55831; Thymidylate synthase/dCMP hydroxymethylase; 1.
DR PROSITE; PS00091; THYMIDYLATE_SYNTHASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Direct protein sequencing; Methyltransferase;
KW Nucleotide biosynthesis; Transferase.
FT CHAIN 1..316
FT /note="Thymidylate synthase"
FT /id="PRO_0000140967"
FT ACT_SITE 198
FT /note="Nucleophile"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00008"
FT BINDING 23
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:0000255|HAMAP-Rule:MF_00008"
FT BINDING 178..179
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00008"
FT BINDING 218..221
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:0000255|HAMAP-Rule:MF_00008"
FT BINDING 221
FT /ligand="(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:15636"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00008"
FT BINDING 229
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:0000255|HAMAP-Rule:MF_00008"
FT BINDING 259..261
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:0000255|HAMAP-Rule:MF_00008"
FT BINDING 315
FT /ligand="(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:15636"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00008"
FT HELIX 4..16
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 18..22
FT /evidence="ECO:0007829|PDB:3IK0"
FT TURN 23..25
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 26..33
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 35..39
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 40..42
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 54..65
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 71..75
FT /evidence="ECO:0007829|PDB:3IK0"
FT TURN 76..78
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 83..90
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 93..95
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 98..100
FT /evidence="ECO:0007829|PDB:1VZC"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:1VZC"
FT HELIX 104..110
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 112..131
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 133..139
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 143..145
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 146..151
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:3BNZ"
FT STRAND 156..158
FT /evidence="ECO:0007829|PDB:2G8D"
FT HELIX 163..173
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 174..176
FT /evidence="ECO:0007829|PDB:1LCB"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:3IK0"
FT TURN 187..192
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 193..195
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 198..207
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 210..221
FT /evidence="ECO:0007829|PDB:3IK0"
FT TURN 222..224
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 225..244
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 247..261
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 262..264
FT /evidence="ECO:0007829|PDB:1JMG"
FT HELIX 265..271
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 281..284
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:3IK0"
FT HELIX 296..298
FT /evidence="ECO:0007829|PDB:3IK0"
FT STRAND 299..302
FT /evidence="ECO:0007829|PDB:3IK0"
SQ SEQUENCE 316 AA; 36580 MW; 4C391722044FF0A5 CRC64;
MLEQPYLDLA KKVLDEGHFK PDRTHTGTYS IFGHQMRFDL SKGFPLLTTK KVPFGLIKSE
LLWFLHGDTN IRFLLQHRNH IWDEWAFEKW VKSDEYHGPD MTDFGHRSQK DPEFAAVYHE
EMAKFDDRVL HDDAFAAKYG DLGLVYGSQW RAWHTSKGDT IDQLGDVIEQ IKTHPYSRRL
IVSAWNPEDV PTMALPPCHT LYQFYVNDGK LSLQLYQRSA DIFLGVPFNI ASYALLTHLV
AHECGLEVGE FIHTFGDAHL YVNHLDQIKE QLSRTPRPAP TLQLNPDKHD IFDFDMKDIK
LLNYDPYPAI KAPVAV
//
