ID TYSY_RAT Reviewed; 307 AA.
AC P45352; A0JN23;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 27-MAR-2024, entry version 161.
DE RecName: Full=Thymidylate synthase;
DE Short=TS;
DE Short=TSase;
DE EC=2.1.1.45 {ECO:0000305|PubMed:9894005};
GN Name=Tyms;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7711067; DOI=10.1016/0167-4781(95)00008-5;
RA Ciesla J., Weiner K.X., Weiner R.S., Reston J.T., Maley G.F., Maley F.;
RT "Isolation and expression of rat thymidylate synthase cDNA: phylogenetic
RT comparison with human and mouse thymidylate synthases.";
RL Biochim. Biophys. Acta 1261:233-242(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3] {ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEX WITH DUMP, CATALYTIC
RP ACTIVITY, SUBUNIT, AND FUNCTION.
RX PubMed=9894005; DOI=10.1021/bi981881d;
RA Sotelo-Mundo R.R., Ciesla J., Dzik J.M., Rode W., Maley F., Maley G.F.,
RA Hardy L.W., Montfort W.R.;
RT "Crystal structures of rat thymidylate synthase inhibited by Tomudex, a
RT potent anticancer drug.";
RL Biochemistry 38:1087-1094(1999).
CC -!- FUNCTION: Catalyzes the reductive methylation of 2'-deoxyuridine 5'-
CC monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the
CC cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-
CC carbon donor and reductant and contributes to the de novo mitochondrial
CC thymidylate biosynthesis pathway. {ECO:0000305|PubMed:9894005}.
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:0000305|PubMed:9894005};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12105;
CC Evidence={ECO:0000305|PubMed:9894005};
CC -!- PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.
CC {ECO:0000305|PubMed:9894005}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:9894005}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P04818}. Cytoplasm
CC {ECO:0000250|UniProtKB:P04818}. Mitochondrion
CC {ECO:0000250|UniProtKB:P04818}. Mitochondrion matrix
CC {ECO:0000250|UniProtKB:P04818}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:P04818}.
CC -!- SIMILARITY: Belongs to the thymidylate synthase family. {ECO:0000305}.
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DR EMBL; L12138; AAA92340.1; -; mRNA.
DR EMBL; BC126093; AAI26094.1; -; mRNA.
DR PIR; S53715; S53715.
DR RefSeq; NP_062052.1; NM_019179.1.
DR PDB; 1RTS; X-ray; 3.30 A; A/B=1-307.
DR PDB; 2TSR; X-ray; 2.60 A; A/B/C/D=1-307.
DR PDBsum; 1RTS; -.
DR PDBsum; 2TSR; -.
DR AlphaFoldDB; P45352; -.
DR SMR; P45352; -.
DR BioGRID; 247934; 1.
DR STRING; 10116.ENSRNOP00000053086; -.
DR BindingDB; P45352; -.
DR ChEMBL; CHEMBL4341; -.
DR DrugCentral; P45352; -.
DR PhosphoSitePlus; P45352; -.
DR jPOST; P45352; -.
DR PaxDb; 10116-ENSRNOP00000053086; -.
DR Ensembl; ENSRNOT00000056243.5; ENSRNOP00000053086.2; ENSRNOG00000037225.5.
DR Ensembl; ENSRNOT00055012922; ENSRNOP00055010305; ENSRNOG00055007718.
DR Ensembl; ENSRNOT00060008051; ENSRNOP00060006026; ENSRNOG00060004837.
DR Ensembl; ENSRNOT00065014859; ENSRNOP00065011108; ENSRNOG00065009297.
DR GeneID; 29261; -.
DR KEGG; rno:29261; -.
DR AGR; RGD:3921; -.
DR CTD; 7298; -.
DR RGD; 3921; Tyms.
DR eggNOG; KOG0673; Eukaryota.
DR GeneTree; ENSGT00390000014786; -.
DR HOGENOM; CLU_021669_0_2_1; -.
DR InParanoid; P45352; -.
DR OMA; IVYELLW; -.
DR OrthoDB; 1118873at2759; -.
DR PhylomeDB; P45352; -.
DR TreeFam; TF353027; -.
DR Reactome; R-RNO-499943; Interconversion of nucleotide di- and triphosphates.
DR SABIO-RK; P45352; -.
DR UniPathway; UPA00575; -.
DR EvolutionaryTrace; P45352; -.
DR PRO; PR:P45352; -.
DR Proteomes; UP000002494; Chromosome 9.
DR Bgee; ENSRNOG00000037225; Expressed in thymus and 19 other cell types or tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005542; F:folic acid binding; IDA:RGD.
DR GO; GO:1901363; F:heterocyclic compound binding; IPI:RGD.
DR GO; GO:0003729; F:mRNA binding; IPI:RGD.
DR GO; GO:0000900; F:mRNA regulatory element binding translation repressor activity; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:RGD.
DR GO; GO:1990825; F:sequence-specific mRNA binding; ISO:RGD.
DR GO; GO:0004799; F:thymidylate synthase activity; IDA:RGD.
DR GO; GO:0051216; P:cartilage development; IEP:RGD.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0048589; P:developmental growth; IEP:RGD.
DR GO; GO:0006231; P:dTMP biosynthetic process; IDA:RGD.
DR GO; GO:0006235; P:dTTP biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0060574; P:intestinal epithelial cell maturation; IEP:RGD.
DR GO; GO:0097421; P:liver regeneration; IEP:RGD.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0017148; P:negative regulation of translation; ISO:RGD.
DR GO; GO:0006206; P:pyrimidine nucleobase metabolic process; IEP:RGD.
DR GO; GO:0006417; P:regulation of translation; IDA:RGD.
DR GO; GO:0034097; P:response to cytokine; IEP:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0051593; P:response to folic acid; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR GO; GO:0046683; P:response to organophosphorus; ISO:RGD.
DR GO; GO:0032570; P:response to progesterone; IEP:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEP:RGD.
DR GO; GO:0033189; P:response to vitamin A; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; ISO:RGD.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; IEP:RGD.
DR GO; GO:0019860; P:uracil metabolic process; IEP:RGD.
DR CDD; cd00351; TS_Pyrimidine_HMase; 1.
DR DisProt; DP02739; -.
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:SF2; 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; Isopeptide bond; Membrane; Methyltransferase;
KW Mitochondrion; Mitochondrion inner membrane; Nucleotide biosynthesis;
KW Nucleus; Phosphoprotein; Reference proteome; Transferase; Ubl conjugation.
FT CHAIN 1..307
FT /note="Thymidylate synthase"
FT /id="PRO_0000140903"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 189
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:P0A884"
FT BINDING 44
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:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 169..170
FT /ligand="dUMP"
FT /ligand_id="ChEBI:CHEBI:246422"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 189..190
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:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 209..212
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:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 212
FT /ligand="(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:15636"
FT /evidence="ECO:0000250|UniProtKB:P0A884"
FT BINDING 220
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:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 250..252
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:0000269|PubMed:9894005,
FT ECO:0007744|PDB:1RTS, ECO:0007744|PDB:2TSR"
FT BINDING 306
FT /ligand="(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:15636"
FT /evidence="ECO:0000250|UniProtKB:P0A884"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04818"
FT CROSSLNK 286
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P04818"
FT CROSSLNK 302
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P04818"
FT HELIX 24..37
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 39..41
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:1RTS"
FT STRAND 49..60
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 75..86
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 93..96
FT /evidence="ECO:0007829|PDB:2TSR"
FT TURN 97..99
FT /evidence="ECO:0007829|PDB:2TSR"
FT TURN 102..104
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 109..114
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:1RTS"
FT HELIX 129..134
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 154..164
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 172..174
FT /evidence="ECO:0007829|PDB:2TSR"
FT TURN 178..180
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 181..183
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 189..198
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 201..212
FT /evidence="ECO:0007829|PDB:2TSR"
FT TURN 213..215
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 216..235
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 238..252
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 253..255
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 256..264
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 272..275
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 282..284
FT /evidence="ECO:0007829|PDB:2TSR"
FT HELIX 287..289
FT /evidence="ECO:0007829|PDB:2TSR"
FT STRAND 290..293
FT /evidence="ECO:0007829|PDB:2TSR"
SQ SEQUENCE 307 AA; 35017 MW; 159F564D347B2B52 CRC64;
MLVEGSELQS GAQQPRTEAP QHGELQYLRQ VEHIMRCGFK KEDRTGTGTL SVFGMQARYS
LRDEFPLLTT KRVFWKGVLE ELLWFIKGST NAKELSSKGV RIWDANGSRD FLDSLGFSAR
QEGDLGPVYG FQWRHFGADY KDMDSDYSGQ GVDQLQKVID TIKTNPDDRR IIMCAWNPKD
LPLMALPPCH ALCQFYVVNG ELSCQLYQRS GDMGLGVPFN IASYALLTYM IAHITGLQPG
DFVHTLGDAH IYLNHIEPLK IQLQREPRPF PKLRILRKVE TIDDFKVEDF QIEGYNPHPT
IKMEMAV
//
