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 02-SEP-2026, entry version 170. DE RecName: Full=Thymidylate synthase {ECO:0000305}; DE Short=TS; DE Short=TSase; DE EC=2.1.1.45 {ECO:0000305|PubMed:9894005}; GN Name=Tyms {ECO:0000312|RGD:3921}; 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 (Probable). Contributes to the mitochondrial CC and nuclear de novo thymidylate biosynthesis pathway (By similarity). CC {ECO:0000250|UniProtKB:P04818, ECO:0000305|PubMed:9894005}. CC -!- CATALYTIC ACTIVITY: CC Reaction=dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 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 (PubMed:9894005). Part of the de novo thymidylate CC synthesis complex composed at least by SHMT1, DHFR and TYMS. Interacts CC with SHMT1; this interaction is DNA-dependent and mediates TYMS co- CC localization with LMNB1 (By similarity). {ECO:0000250|UniProtKB:P04818, CC 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}. Note=Localized to the nucleus during S CC and G2/M phasesof the cell cycle. As a component of the de novo CC thymidylate synthesis complex, localizes specifically to replication CC forks during DNA synthesis (By similarity). CC {ECO:0000250|UniProtKB:P04818}. CC -!- PTM: Sumoylated by UBE2I/UBC9. {ECO:0000250|UniProtKB:P04818}. CC -!- SIMILARITY: Belongs to the thymidylate synthase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L12138; AAA92340.1; -; mRNA. DR EMBL; BC126093; AAI26094.1; -; mRNA. DR PIR; S53715; S53715. DR RefSeq; NP_062052.1; NM_019179.2. 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 AlphaFoldDB; P45352; -. DR MDRepo; P45352; -. DR SMR; P45352; -. DR BioGRID; 247934; 1. DR FunCoup; P45352; 1514. 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; ENSRNOT00000093931.2; ENSRNOP00000084093.2; ENSRNOG00000037225.6. 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; AYGRFWR; -. DR OrthoDB; 766at2759; -. DR PhylomeDB; P45352; -. 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 ExpressionAtlas; P45352; baseline and differential. 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; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005657; C:replication fork; ISO:RGD. 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:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; ISO: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:0006260; P:DNA replication; ISO: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: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: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:0019860; P:uracil metabolic process; IEP:RGD. DR CDD; cd00351; TS_Pyrimidine_HMase; 1. DR DisProt; DP02739; -. DR FunFam; 3.30.572.10:FF:000007; thymidylate synthase isoform X2; 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; NF002497; PRK01827.1-3; 1. 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. DR PDBsum; 1RTS; -. DR PDBsum; 2TSR; -. 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 COMPBIAS 7..16 FT /note="Polar residues" 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 138..140 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 HELIX 266..270 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 //