ID TYSY_HUMAN Reviewed; 313 AA. AC P04818; Q8WYK3; Q8WYK4; DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 02-SEP-2026, entry version 245. DE RecName: Full=Thymidylate synthase {ECO:0000305}; DE Short=TS; DE Short=TSase; DE EC=2.1.1.45 {ECO:0000269|PubMed:11278511}; GN Name=TYMS {ECO:0000312|HGNC:HGNC:12441}; Synonyms=TS; GN ORFNames=OK/SW-cl.29; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2987839; DOI=10.1093/nar/13.6.2035; RA Takeishi K., Kaneda S., Ayusawa D., Shimizu K., Gotoh O., Seno T.; RT "Nucleotide sequence of a functional cDNA for human thymidylate synthase."; RL Nucleic Acids Res. 13:2035-2043(1985). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2243092; DOI=10.1016/s0021-9258(17)30501-x; RA Kaneda S., Nalbantoglu J., Takeishi K., Shimizu K., Gotoh O., Seno T., RA Ayusawa D.; RT "Structural and functional analysis of the human thymidylate synthase RT gene."; RL J. Biol. Chem. 265:20277-20284(1990). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND ALTERNATIVE SPLICING. RX PubMed=12706868; DOI=10.1016/s0304-3835(03)00005-3; RA Hisatomi H., Tanemura H., Iizuka T., Katsumata K., Nagao K., Sumida H., RA Udagawa H., Hikiji K.; RT "Differential alternative splicing expressions of thymidylate synthase RT isoforms."; RL Cancer Lett. 193:127-131(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Colon adenocarcinoma; RA Shichijo S., Itoh K.; RT "Identification of immuno-peptidmics that are recognized by tumor-reactive RT CTL generated from TIL of colon cancer patients."; RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16177791; DOI=10.1038/nature03983; RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J., RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.; RT "DNA sequence and analysis of human chromosome 18."; RL Nature 437:551-555(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Bone marrow, Placenta, and Skin; 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 [8] RP NUCLEOTIDE SEQUENCE OF 1-68. RX PubMed=2532645; DOI=10.1093/oxfordjournals.jbchem.a122898; RA Takeishi K., Kaneda S., Ayusawa D., Shimizu K., Gotoh O., Seno T.; RT "Human thymidylate synthase gene: isolation of phage clones which cover a RT functionally active gene and structural analysis of the region upstream RT from the translation initiation codon."; RL J. Biochem. 106:575-583(1989). RN [9] RP PROTEIN SEQUENCE OF 2-25. RX PubMed=3839505; DOI=10.1093/oxfordjournals.jbchem.a135125; RA Shimizu K., Ayusawa D., Takeishi K., Seno T.; RT "Purification and NH2-terminal amino acid sequence of human thymidylate RT synthase in an overproducing transformant of mouse FM3A cells."; RL J. Biochem. 97:845-850(1985). RN [10] RP PROTEIN SEQUENCE OF 2-10. RX PubMed=2656695; DOI=10.1016/s0021-9258(18)60506-x; RA Davisson V.J., Sirawaraporn W., Santi D.V.; RT "Expression of human thymidylate synthase in Escherichia coli."; RL J. Biol. Chem. 264:9145-9148(1989). RN [11] RP SUMOYLATION. RX PubMed=18067453; DOI=10.1515/cclm.2007.355; RA Anderson D.D., Woeller C.F., Stover P.J.; RT "Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate RT synthase and dihydrofolate reductase."; RL Clin. Chem. Lab. Med. 45:1760-1763(2007). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=21876188; DOI=10.1073/pnas.1103623108; RA Anderson D.D., Quintero C.M., Stover P.J.; RT "Identification of a de novo thymidylate biosynthesis pathway in mammalian RT mitochondria."; RL Proc. Natl. Acad. Sci. U.S.A. 108:15163-15168(2011). RN [15] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SHMT1. RX PubMed=22235121; DOI=10.1074/jbc.m111.333120; RA Anderson D.D., Woeller C.F., Chiang E.P., Shane B., Stover P.J.; RT "Serine hydroxymethyltransferase anchors de novo thymidylate synthesis RT pathway to nuclear lamina for DNA synthesis."; RL J. Biol. Chem. 287:7051-7062(2012). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [18] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-287; LYS-292 AND LYS-308, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [19] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS). RX PubMed=8845352; DOI=10.1021/bi00050a007; RA Schiffer C.A., Clifton I.J., Davisson V.J., Santi D.V., Stroud R.M.; RT "Crystal structure of human thymidylate synthase: a structural mechanism RT for guiding substrates into the active site."; RL Biochemistry 34:16279-16287(1995). RN [20] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS). RX PubMed=11329255; DOI=10.1021/bi002413i; RA Phan J., Koli S., Minor W., Dunlap R.B., Berger S.H., Lebioda L.; RT "Human thymidylate synthase is in the closed conformation when complexed RT with dUMP and raltitrexed, an antifolate drug."; RL Biochemistry 40:1897-1902(2001). RN [21] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=11278511; DOI=10.1074/jbc.m009493200; RA Phan J., Steadman D.J., Koli S., Ding W.C., Minor W., Dunlap R.B., RA Berger S.H., Lebioda L.; RT "Structure of human thymidylate synthase suggests advantages of RT chemotherapy with noncompetitive inhibitors."; RL J. Biol. Chem. 276:14170-14177(2001). RN [22] RP VARIANTS DKCD LYS-87; 115-ARG--VAL-313 DEL; HIS-160 AND 271-ARG--VAL-313 RP DEL, CHARACTERIZATION OF VARIANT DKCD 115-ARG--VAL-313 DEL, AND INVOLVEMENT RP IN DKCD. RX PubMed=35931051; DOI=10.1016/j.ajhg.2022.06.014; RA Tummala H., Walne A., Buccafusca R., Alnajar J., Szabo A., Robinson P., RA McConkie-Rosell A., Wilson M., Crowley S., Kinsler V., Ewins A.M., RA Madapura P.M., Patel M., Pontikos N., Codd V., Vulliamy T., Dokal I.; RT "Germline thymidylate synthase deficiency impacts nucleotide metabolism and RT causes dyskeratosis congenita."; RL Am. J. Hum. Genet. 109:1472-1483(2022). 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 mitochondrial and CC nuclear de novo thymidylate biosynthesis pathway. CC {ECO:0000269|PubMed:11278511, ECO:0000269|PubMed:21876188, CC ECO:0000269|PubMed:22235121}. 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:0000269|PubMed:11278511}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12105; CC Evidence={ECO:0000305|PubMed:11278511}; CC -!- PATHWAY: Pyrimidine metabolism; dTTP biosynthesis. CC {ECO:0000305|PubMed:11278511}. CC -!- SUBUNIT: Homodimer. Part of the de novo thymidylate synthesis complex CC composed at least by SHMT1, DHFR and TYMS (PubMed:22235121). Interacts CC with SHMT1; this interaction is DNA-dependent and mediates TYMS co- CC localization with LMNB1 (PubMed:22235121). CC {ECO:0000250|UniProtKB:P45352, ECO:0000269|PubMed:22235121}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21876188, CC ECO:0000269|PubMed:22235121}. Cytoplasm {ECO:0000269|PubMed:21876188}. CC Mitochondrion {ECO:0000269|PubMed:21876188}. Mitochondrion matrix CC {ECO:0000269|PubMed:21876188}. Mitochondrion inner membrane CC {ECO:0000269|PubMed:21876188}. Note=Localized to the nucleus during S CC and G2/M phases of the cell cycle. As a component of the de novo CC thymidylate synthesis complex, localizes specifically to replication CC forks during DNA synthesis (PubMed:22235121). CC {ECO:0000269|PubMed:22235121}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P04818-1; Sequence=Displayed; CC Name=2; Synonyms=delta4; CC IsoId=P04818-2; Sequence=VSP_047746; CC Name=3; Synonyms=delta2+3; CC IsoId=P04818-3; Sequence=VSP_047745; CC -!- PTM: Sumoylated by UBE2I/UBC9. {ECO:0000269|PubMed:18067453}. CC -!- DISEASE: Dyskeratosis congenita, digenic (DKCD) [MIM:620040]: A form of CC dyskeratosis congenita, a rare multisystem disorder caused by defective CC telomere maintenance. It is characterized by progressive bone marrow CC failure, and the clinical triad of reticulated skin hyperpigmentation, CC nail dystrophy, and mucosal leukoplakia. Common but variable features CC include premature graying, aplastic anemia, low platelets, CC osteoporosis, pulmonary fibrosis, and liver fibrosis among others. CC Early mortality is often associated with bone marrow failure, CC infections, fatal pulmonary complications, or malignancy. DKCD CC transmission pattern is consistent with digenic inheritance. CC {ECO:0000269|PubMed:35931051}. Note=The disease is caused by variants CC affecting distinct genetic loci, including the gene represented in this CC entry. TYMS germline variants in the presence of a common ENOSF1 CC haplotype (defined by rs699517, rs2790 and rs1512643) result in severe CC thymidylate synthase deficiency and disease. The pathogenic mechanism CC involves increased expression of ENOSF1 relative to TYMS, and post- CC transcriptional inhibition of TYMS translation through ENOSF1-TYMS RNA- CC RNA interactions. {ECO:0000269|PubMed:35931051}. CC -!- MISCELLANEOUS: [Isoform 2]: Expressed both in normal and cancerous CC tissues. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 3]: Expressed only in cancerous tissues. CC {ECO:0000305}. 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; X02308; CAA26178.1; -; mRNA. DR EMBL; D00596; BAA00472.1; -; Genomic_DNA. DR EMBL; AB077207; BAB83676.1; -; mRNA. DR EMBL; AB077208; BAB83677.1; -; mRNA. DR EMBL; AB062290; BAB93473.1; -; mRNA. DR EMBL; AP001178; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471113; EAX01716.1; -; Genomic_DNA. DR EMBL; CH471113; EAX01720.1; -; Genomic_DNA. DR EMBL; BC002567; AAH02567.1; -; mRNA. DR EMBL; BC013919; AAH13919.1; -; mRNA. DR EMBL; BC083512; AAH83512.1; -; mRNA. DR EMBL; D00517; BAA00404.1; -; Genomic_DNA. DR CCDS; CCDS11821.1; -. [P04818-1] DR CCDS; CCDS86658.1; -. [P04818-2] DR CCDS; CCDS86659.1; -. [P04818-3] DR PIR; A23047; YXHUT. DR RefSeq; NP_001062.1; NM_001071.4. [P04818-1] DR RefSeq; NP_001341796.1; NM_001354867.2. [P04818-2] DR RefSeq; NP_001341797.1; NM_001354868.2. [P04818-3] DR PDB; 1HVY; X-ray; 1.90 A; A/B/C/D=26-313. DR PDB; 1HW3; X-ray; 2.00 A; A=1-313. DR PDB; 1HW4; X-ray; 2.06 A; A=1-313. DR PDB; 1HZW; X-ray; 2.00 A; A/B=26-313. DR PDB; 1I00; X-ray; 2.50 A; A/B=26-313. DR PDB; 1JU6; X-ray; 2.89 A; A/B/C/D=1-313. DR PDB; 1JUJ; X-ray; 3.00 A; A/B/C/D=1-313. DR PDB; 1YPV; X-ray; 1.80 A; A=1-313. DR PDB; 2ONB; X-ray; 2.70 A; A=1-313. DR PDB; 2RD8; X-ray; 2.50 A; A/B=1-313. DR PDB; 2RDA; X-ray; 2.67 A; A/B/C/D/E/F=1-313. DR PDB; 3EAW; X-ray; 1.86 A; X=1-313. DR PDB; 3EBU; X-ray; 2.05 A; A=1-313. DR PDB; 3ED7; X-ray; 1.56 A; A=26-313. DR PDB; 3EDW; X-ray; 1.75 A; X=1-313. DR PDB; 3EF9; X-ray; 3.20 A; A=1-313. DR PDB; 3EGY; X-ray; 2.18 A; X=1-313. DR PDB; 3EHI; X-ray; 2.00 A; X=1-313. DR PDB; 3EJL; X-ray; 3.20 A; A/B/C/D=1-313. DR PDB; 3GG5; X-ray; 2.77 A; A/B/C/D=1-313. DR PDB; 3GH0; X-ray; 1.56 A; A=1-313. DR PDB; 3GH2; X-ray; 1.75 A; X=1-313. DR PDB; 3H9K; X-ray; 2.65 A; A/B/C/D/E=1-313. DR PDB; 3HB8; X-ray; 2.74 A; A/B/C/D/E=1-313. DR PDB; 3N5E; X-ray; 2.26 A; A/B=1-313. DR PDB; 3N5G; X-ray; 2.27 A; A=1-313. DR PDB; 3OB7; X-ray; 2.75 A; A/B/C/D/E=1-313. DR PDB; 4E28; X-ray; 2.30 A; A=1-313. DR PDB; 4FGT; X-ray; 2.00 A; A=1-313. DR PDB; 4G2O; X-ray; 2.25 A; X=1-313. DR PDB; 4G6W; X-ray; 2.30 A; X=1-313. DR PDB; 4GD7; X-ray; 2.29 A; A=1-313. DR PDB; 4GYH; X-ray; 3.00 A; A=1-313. DR PDB; 4H1I; X-ray; 3.10 A; A/B/C/D=1-313. DR PDB; 4JEF; X-ray; 2.31 A; A=26-311. DR PDB; 4KPW; X-ray; 2.03 A; A=1-313. DR PDB; 4O1U; X-ray; 2.26 A; A/B=1-313. DR PDB; 4O1X; X-ray; 2.32 A; A/B/C/D=1-313. DR PDB; 4UP1; X-ray; 2.99 A; A/B/C/D=1-313. DR PDB; 5HS3; X-ray; 3.10 A; A/B/C/D/E/F=26-313. DR PDB; 5WRN; X-ray; 2.39 A; A/B/C/D/E/F=26-313. DR PDB; 5X4W; X-ray; 2.10 A; A=1-313. DR PDB; 5X4X; X-ray; 2.31 A; A=1-313. DR PDB; 5X4Y; X-ray; 2.20 A; A=1-313. DR PDB; 5X5A; X-ray; 2.39 A; A/B/C/D/E/F=26-313. DR PDB; 5X5D; X-ray; 2.00 A; A/B/C/D/E/F=26-313. DR PDB; 5X5Q; X-ray; 2.79 A; A/B/C/D/E/F=26-313. DR PDB; 5X66; X-ray; 1.99 A; A/B/C/D/E/F=26-313. DR PDB; 5X67; X-ray; 2.13 A; A/B=26-313. DR PDB; 5X69; X-ray; 2.69 A; A/B/C/D/E/F=26-313. DR PDB; 6OJU; X-ray; 2.88 A; A/B/C/D=1-313. DR PDB; 6OJV; X-ray; 2.59 A; A/B/C/D=1-313. DR PDB; 6PF3; X-ray; 2.39 A; A/B/C/D=26-313. DR PDB; 6PF4; X-ray; 2.85 A; A/B/C/D=26-313. DR PDB; 6PF5; X-ray; 2.39 A; A/B/C/D=26-313. DR PDB; 6PF6; X-ray; 2.50 A; A/B/C/D=1-313. DR PDB; 6QXG; X-ray; 2.08 A; A/B/C=1-313. DR PDB; 6QXH; X-ray; 2.04 A; A/B/C=1-313. DR PDB; 6QYQ; X-ray; 2.25 A; A/B/C/D=1-313. DR PDB; 6R2E; X-ray; 2.55 A; A/B/C/D/E/F/G/H=1-313. DR PDB; 6ZXO; X-ray; 2.60 A; A/B/C/D/E/F=1-313. DR AlphaFoldDB; P04818; -. DR MDRepo; P04818; -. DR SMR; P04818; -. DR BioGRID; 113149; 120. DR CORUM; P04818; -. DR FunCoup; P04818; 2448. DR IntAct; P04818; 29. DR MINT; P04818; -. DR NDEx; IQUERY-CP-TYMS; 19 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000315644; -. DR BindingDB; P04818; -. DR ChEMBL; CHEMBL1952; -. DR DrugBank; DB03541; 10-Propargyl-5,8-Dideazafolic Acid. DR DrugBank; DB07577; 2,4-Diamino-5-phenyl-6-ethylpyrimidine. DR DrugBank; DB08734; 6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE. DR DrugBank; DB01101; Capecitabine. DR DrugBank; DB03800; Deoxyuridine monophosphate. DR DrugBank; DB00322; Floxuridine. DR DrugBank; DB00544; Fluorouracil. DR DrugBank; DB05308; Folitixorin calcium. DR DrugBank; DB14859; Fosifloxuridine nafalbenamide. DR DrugBank; DB00441; Gemcitabine. DR DrugBank; DB00563; Methotrexate. DR DrugBank; DB08479; N-(3,5-dimethoxyphenyl)imidodicarbonimidic diamide. DR DrugBank; DB08478; N-[2-Chloro-5-(trifluoromethyl)phenyl]imidodicarbonimidic diamide. DR DrugBank; DB05457; OSI-7904L. DR DrugBank; DB00642; Pemetrexed. DR DrugBank; DB06813; Pralatrexate. DR DrugBank; DB00293; Raltitrexed. DR DrugBank; DB04530; S,S-(2-Hydroxyethyl)Thiocysteine. DR DrugBank; DB09256; Tegafur. DR DrugBank; DB09327; Tegafur-uracil. DR DrugBank; DB05116; Thymectacin. DR DrugBank; DB01643; Thymidine monophosphate. DR DrugBank; DB00432; Trifluridine. DR DrugCentral; P04818; -. DR GuidetoPHARMACOLOGY; 2642; -. DR MoonProt; P04818; -. DR GlyGen; P04818; 3 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (2 sites). DR iPTMnet; P04818; -. DR MetOSite; P04818; -. DR PhosphoSitePlus; P04818; -. DR SwissPalm; P04818; -. DR BioMuta; TYMS; -. DR DMDM; 136611; -. DR jPOST; P04818; -. DR MassIVE; P04818; -. DR PaxDb; 9606-ENSP00000315644; -. DR PeptideAtlas; P04818; -. DR ProteomicsDB; 51747; -. [P04818-1] DR ProteomicsDB; 75165; -. DR ProteomicsDB; 75166; -. DR Pumba; P04818; -. DR TopDownProteomics; P04818-1; -. [P04818-1] DR Antibodypedia; 3461; 1290 antibodies from 45 providers. DR DNASU; 7298; -. DR Ensembl; ENST00000323224.7; ENSP00000314727.7; ENSG00000176890.17. [P04818-2] DR Ensembl; ENST00000323250.9; ENSP00000314902.5; ENSG00000176890.17. [P04818-3] DR Ensembl; ENST00000323274.15; ENSP00000315644.10; ENSG00000176890.17. [P04818-1] DR GeneID; 7298; -. DR KEGG; hsa:7298; -. DR MANE-Select; ENST00000323274.15; ENSP00000315644.10; NM_001071.4; NP_001062.1. DR UCSC; uc010dkb.2; human. [P04818-1] DR AGR; HGNC:12441; -. DR CIViC; 7298; 10 evidence items across 5 molecular profiles. DR ClinPGx; PA359; -. DR CTD; 7298; -. DR DisGeNET; 7298; -. DR GeneCards; TYMS; -. DR HGNC; HGNC:12441; TYMS. DR HPA; ENSG00000176890; Tissue enhanced (bone marrow, lymphoid tissue). DR MalaCards; TYMS; -. DR MIM; 188350; gene. DR MIM; 620040; phenotype. DR OpenTargets; ENSG00000176890; -. DR Orphanet; 1775; Dyskeratosis congenita. DR VEuPathDB; HostDB:ENSG00000176890; -. DR eggNOG; KOG0673; Eukaryota. DR GeneTree; ENSGT00390000014786; -. DR HOGENOM; CLU_021669_0_2_1; -. DR InParanoid; P04818; -. DR OMA; AYGRFWR; -. DR OrthoDB; 766at2759; -. DR PAN-GO; P04818; 4 GO annotations based on evolutionary models. DR PhylomeDB; P04818; -. DR BioCyc; MetaCyc:HS11096-MONOMER; -. DR BRENDA; 2.1.1.45; 2681. DR PathwayCommons; P04818; -. DR Reactome; R-HSA-499943; Interconversion of nucleotide di- and triphosphates. DR Reactome; R-HSA-69205; G1/S-Specific Transcription. DR SABIO-RK; P04818; -. DR SignaLink; P04818; -. DR SIGNOR; P04818; -. DR UniPathway; UPA00575; -. DR Agora; ENSG00000176890; -. DR BioGRID-ORCS; 7298; 334 hits in 1189 CRISPR screens. DR ChiTaRS; TYMS; human. DR EvolutionaryTrace; P04818; -. DR GeneWiki; Thymidylate_synthase; -. DR GenomeRNAi; 7298; -. DR Pharos; P04818; Tclin. DR PRO; PR:P04818; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P04818; protein. DR Bgee; ENSG00000176890; Expressed in ventricular zone and 184 other cell types or tissues. DR ExpressionAtlas; P04818; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005657; C:replication fork; IDA:UniProt. DR GO; GO:0005542; F:folic acid binding; IC:BHF-UCL. DR GO; GO:0000900; F:mRNA regulatory element binding translation repressor activity; IDA:CAFA. DR GO; GO:1990825; F:sequence-specific mRNA binding; IDA:CAFA. DR GO; GO:0004799; F:thymidylate synthase activity; IDA:CAFA. DR GO; GO:0006207; P:'de novo' pyrimidine nucleobase biosynthetic process; IDA:UniProt. DR GO; GO:0071897; P:DNA biosynthetic process; IC:BHF-UCL. DR GO; GO:0006260; P:DNA replication; IDA:UniProt. DR GO; GO:0006231; P:dTMP biosynthetic process; IDA:CAFA. DR GO; GO:0006235; P:dTTP biosynthetic process; IEA:UniProtKB-UniPathway. DR GO; GO:0017148; P:negative regulation of translation; IDA:CAFA. DR GO; GO:0035999; P:tetrahydrofolate interconversion; IDA:BHF-UCL. DR CDD; cd00351; TS_Pyrimidine_HMase; 1. DR DisProt; DP00073; -. 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; 1HVY; -. DR PDBsum; 1HW3; -. DR PDBsum; 1HW4; -. DR PDBsum; 1HZW; -. DR PDBsum; 1I00; -. DR PDBsum; 1JU6; -. DR PDBsum; 1JUJ; -. DR PDBsum; 1YPV; -. DR PDBsum; 2ONB; -. DR PDBsum; 2RD8; -. DR PDBsum; 2RDA; -. DR PDBsum; 3EAW; -. DR PDBsum; 3EBU; -. DR PDBsum; 3ED7; -. DR PDBsum; 3EDW; -. DR PDBsum; 3EF9; -. DR PDBsum; 3EGY; -. DR PDBsum; 3EHI; -. DR PDBsum; 3EJL; -. DR PDBsum; 3GG5; -. DR PDBsum; 3GH0; -. DR PDBsum; 3GH2; -. DR PDBsum; 3H9K; -. DR PDBsum; 3HB8; -. DR PDBsum; 3N5E; -. DR PDBsum; 3N5G; -. DR PDBsum; 3OB7; -. DR PDBsum; 4E28; -. DR PDBsum; 4FGT; -. DR PDBsum; 4G2O; -. DR PDBsum; 4G6W; -. DR PDBsum; 4GD7; -. DR PDBsum; 4GYH; -. DR PDBsum; 4H1I; -. DR PDBsum; 4JEF; -. DR PDBsum; 4KPW; -. DR PDBsum; 4O1U; -. DR PDBsum; 4O1X; -. DR PDBsum; 4UP1; -. DR PDBsum; 5HS3; -. DR PDBsum; 5WRN; -. DR PDBsum; 5X4W; -. DR PDBsum; 5X4X; -. DR PDBsum; 5X4Y; -. DR PDBsum; 5X5A; -. DR PDBsum; 5X5D; -. DR PDBsum; 5X5Q; -. DR PDBsum; 5X66; -. DR PDBsum; 5X67; -. DR PDBsum; 5X69; -. DR PDBsum; 6OJU; -. DR PDBsum; 6OJV; -. DR PDBsum; 6PF3; -. DR PDBsum; 6PF4; -. DR PDBsum; 6PF5; -. DR PDBsum; 6PF6; -. DR PDBsum; 6QXG; -. DR PDBsum; 6QXH; -. DR PDBsum; 6QYQ; -. DR PDBsum; 6R2E; -. DR PDBsum; 6ZXO; -. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Direct protein sequencing; KW Disease variant; Dyskeratosis congenita; Isopeptide bond; Membrane; KW Methyltransferase; Mitochondrion; Mitochondrion inner membrane; KW Nucleotide biosynthesis; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Transferase; KW Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|PubMed:2656695, FT ECO:0000269|PubMed:3839505" FT CHAIN 2..313 FT /note="Thymidylate synthase" FT /id="PRO_0000140901" FT REGION 1..28 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 18..28 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 195 FT /note="Nucleophile" FT /evidence="ECO:0000250|UniProtKB:P0A884" FT BINDING 50 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:0000250|UniProtKB:P0A884" FT BINDING 175..176 FT /ligand="dUMP" FT /ligand_id="ChEBI:CHEBI:246422" FT /ligand_note="ligand shared between dimeric partners" FT /evidence="ECO:0000250|UniProtKB:P45352" FT BINDING 195..196 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:0000250|UniProtKB:P45352" FT BINDING 215..218 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:0000250|UniProtKB:P45352" FT BINDING 218 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 226 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:0000250|UniProtKB:P0A884" FT BINDING 256..258 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:0000250|UniProtKB:P45352" FT BINDING 312 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 114 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 287 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 292 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 308 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 69..151 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:12706868" FT /id="VSP_047745" FT VAR_SEQ 152..185 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12706868" FT /id="VSP_047746" FT VARIANT 87 FT /note="E -> K (in DKCD; uncertain significance; FT dbSNP:rs2144258402)" FT /evidence="ECO:0000269|PubMed:35931051" FT /id="VAR_087693" FT VARIANT 115..313 FT /note="Missing (in DKCD; reduced TYMS levels in patient FT cells)" FT /evidence="ECO:0000269|PubMed:35931051" FT /id="VAR_087694" FT VARIANT 160 FT /note="Q -> H (in DKCD; uncertain significance; FT dbSNP:rs894600614)" FT /evidence="ECO:0000269|PubMed:35931051" FT /id="VAR_087695" FT VARIANT 271..313 FT /note="Missing (in DKCD)" FT /evidence="ECO:0000269|PubMed:35931051" FT /id="VAR_087696" FT HELIX 26..28 FT /evidence="ECO:0007829|PDB:6QYQ" FT HELIX 30..43 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 50..52 FT /evidence="ECO:0007829|PDB:1YPV" FT STRAND 54..66 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 68..70 FT /evidence="ECO:0007829|PDB:3EBU" FT TURN 75..78 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 81..92 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 98..101 FT /evidence="ECO:0007829|PDB:3ED7" FT TURN 103..105 FT /evidence="ECO:0007829|PDB:1HVY" FT TURN 108..110 FT /evidence="ECO:0007829|PDB:1HVY" FT HELIX 111..113 FT /evidence="ECO:0007829|PDB:1HVY" FT HELIX 117..120 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 123..127 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 128..130 FT /evidence="ECO:0007829|PDB:6OJU" FT TURN 132..134 FT /evidence="ECO:0007829|PDB:4E28" FT HELIX 136..141 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 144..146 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 149..151 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:3EHI" FT HELIX 160..170 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 178..181 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 184..186 FT /evidence="ECO:0007829|PDB:3ED7" FT TURN 187..189 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 190..192 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 193..195 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 196..204 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 207..218 FT /evidence="ECO:0007829|PDB:3ED7" FT TURN 219..221 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 222..241 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 244..258 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 259..261 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 262..268 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 272..274 FT /evidence="ECO:0007829|PDB:3EDW" FT HELIX 275..277 FT /evidence="ECO:0007829|PDB:6QXH" FT STRAND 278..281 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 288..290 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 293..295 FT /evidence="ECO:0007829|PDB:3ED7" FT STRAND 296..300 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 303..306 FT /evidence="ECO:0007829|PDB:3ED7" FT HELIX 310..312 FT /evidence="ECO:0007829|PDB:5X67" SQ SEQUENCE 313 AA; 35716 MW; 148D377F19915B6A CRC64; MPVAGSELPR RPLPPAAQER DAEPRPPHGE LQYLGQIQHI LRCGVRKDDR TGTGTLSVFG MQARYSLRDE FPLLTTKRVF WKGVLEELLW FIKGSTNAKE LSSKGVKIWD ANGSRDFLDS LGFSTREEGD LGPVYGFQWR HFGAEYRDME SDYSGQGVDQ LQRVIDTIKT NPDDRRIIMC AWNPRDLPLM ALPPCHALCQ FYVVNSELSC QLYQRSGDMG LGVPFNIASY ALLTYMIAHI TGLKPGDFIH TLGDAHIYLN HIEPLKIQLQ REPRPFPKLR ILRKVEKIDD FKAEDFQIEG YNPHPTIKME MAV //