Thymidylate synthase

Details

Name
Thymidylate synthase
Kind
protein
Synonyms
  • 2.1.1.45
  • TS
  • TSase
Gene Name
TYMS
UniProtKB Entry
P04818Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0036991|Thymidylate synthase
MPVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFG
MQARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDS
LGFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMC
AWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHI
TGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEG
YNPHPTIKMEMAV
Number of residues
313
Molecular Weight
35715.65
Theoretical pI
7.0
GO Classification
Functions
mRNA regulatory element binding translation repressor activity / protein homodimerization activity / sequence-specific mRNA binding
Processes
liver regeneration / methylation / negative regulation of translation / response to xenobiotic stimulus
General Function
Catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to thymidine 5'-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to the de novo mitochondrial thymidylate biosynthesis pathway
Specific Function
folic acid binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0010247|Thymidylate synthase (TYMS)
ATGCCTGTGGCCGGCTCGGAGCTGCCGCGCCGGCCCTTGCCCCCCGCCGCACAGGAGCGG
GACGCCGAGCCGCGTCCGCCGCACGGGGAGCTGCAGTACCTGGGGCAGATCCAACACATC
CTCCGCTGCGGCGTCAGGAAGGACGACCGCACGGGCACCGGCACCCTGTCGGTATTCGGC
ATGCAGGCGCGCTACAGCCTGAGAGATGAATTCCCTCTGCTGACAACCAAACGTGTGTTC
TGGAAGGGTGTTTTGGAGGAGTTGCTGTGGTTTATCAAGGGATCCACAAATGCTAAAGAG
CTGTCTTCCAAGGGAGTGAAAATCTGGGATGCCAATGGATCCCGAGACTTTTTGGACAGC
CTGGGATTCTCCACCAGAGAAGAAGGGGACTTGGGCCCAGTTTATGGCTTCCAGTGGAGG
CATTTTGGGGCAGAATACAGAGATATGGAATCAGATTATTCAGGACAGGGAGTTGACCAA
CTGCAAAGAGTGATTGACACCATCAAAACCAACCCTGACGACAGAAGAATCATCATGTGC
GCTTGGAATCCAAGAGATCTTCCTCTGATGGCGCTGCCTCCATGCCATGCCCTCTGCCAG
TTCTATGTGGTGAACAGTGAGCTGTCCTGCCAGCTGTACCAGAGATCGGGAGACATGGGC
CTCGGTGTGCCTTTCAACATCGCCAGCTACGCCCTGCTCACGTACATGATTGCGCACATC
ACGGGCCTGAAGCCAGGTGACTTTATACACACTTTGGGAGATGCACATATTTACCTGAAT
CACATCGAGCCACTGAAAATTCAGCTTCAGCGAGAACCCAGACCTTTCCCAAAGCTCAGG
ATTCTTCGAAAAGTTGAGAAAATTGATGACTTCAAAGCTGAAGACTTTCAGATTGAAGGG
TACAATCCGCATCCAACTATTAAAATGGAAATGGCTGTTTAG
Chromosome Location
18
Locus
18p11.32
External Identifiers
ResourceLink
UniProtKB IDP04818
UniProtKB Entry NameTYSY_HUMAN
GenBank Protein ID37479
GenBank Gene IDX02308
GeneCard IDTYMS
GenAtlas IDTYMS
HGNC IDHGNC:12441
PDB ID(s)1HVY, 1HW3, 1HW4, 1HZW, 1I00, 1JU6, 1JUJ, 1YPV, 2ONB, 2RD8, 2RDA, 3EAW, 3EBU, 3ED7, 3EDW, 3EF9, 3EGY, 3EHI, 3EJL, 3GG5, 3GH0, 3GH2, 3H9K, 3HB8, 3N5E, 3N5G, 3OB7, 4E28, 4FGT, 4G2O, 4G6W, 4GD7, 4GYH, 4H1I, 4JEF, 4KPW, 4O1U, 4O1X, 4UP1, 5HS3, 5WRN, 5X4W, 5X4X, 5X4Y, 5X5A, 5X5D, 5X5Q, 5X66, 5X67, 5X69, 6OJU, 6OJV, 6PF3, 6PF4, 6PF5, 6PF6, 6QXG, 6QXH, 6QYQ, 6R2E, 6ZXO
KEGG IDhsa:7298
IUPHAR/Guide To Pharmacology ID2642
NCBI Gene ID7298
General References
  1. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T: Nucleotide sequence of a functional cDNA for human thymidylate synthase. Nucleic Acids Res. 1985 Mar 25;13(6):2035-43. [Article]
  2. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D: Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990 Nov 25;265(33):20277-84. [Article]
  3. Hisatomi H, Tanemura H, Iizuka T, Katsumata K, Nagao K, Sumida H, Udagawa H, Hikiji K: Differential alternative splicing expressions of thymidylate synthase isoforms. Cancer Lett. 2003 Apr 25;193(2):127-31. [Article]
  4. Nusbaum C, Zody MC, Borowsky ML, Kamal M, Kodira CD, Taylor TD, Whittaker CA, Chang JL, Cuomo CA, Dewar K, FitzGerald MG, Yang X, Abouelleil A, Allen NR, Anderson S, Bloom T, Bugalter B, Butler J, Cook A, DeCaprio D, Engels R, Garber M, Gnirke A, Hafez N, Hall JL, Norman CH, Itoh T, Jaffe DB, Kuroki Y, Lehoczky J, Lui A, Macdonald P, Mauceli E, Mikkelsen TS, Naylor JW, Nicol R, Nguyen C, Noguchi H, O'Leary SB, O'Neill K, Piqani B, Smith CL, Talamas JA, Topham K, Totoki Y, Toyoda A, Wain HM, Young SK, Zeng Q, Zimmer AR, Fujiyama A, Hattori M, Birren BW, Sakaki Y, Lander ES: DNA sequence and analysis of human chromosome 18. Nature. 2005 Sep 22;437(7058):551-5. [Article]
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  6. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T: Human thymidylate synthase gene: isolation of phage clones which cover a functionally active gene and structural analysis of the region upstream from the translation initiation codon. J Biochem. 1989 Oct;106(4):575-83. [Article]
  7. Shimizu K, Ayusawa D, Takeishi K, Seno T: Purification and NH2-terminal amino acid sequence of human thymidylate synthase in an overproducing transformant of mouse FM3A cells. J Biochem. 1985 Mar;97(3):845-50. [Article]
  8. Davisson VJ, Sirawaraporn W, Santi DV: Expression of human thymidylate synthase in Escherichia coli. J Biol Chem. 1989 Jun 5;264(16):9145-8. [Article]
  9. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [Article]
  10. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [Article]
  11. Anderson DD, Quintero CM, Stover PJ: Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi: 10.1073/pnas.1103623108. Epub 2011 Aug 26. [Article]
  12. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]
  13. Schiffer CA, Clifton IJ, Davisson VJ, Santi DV, Stroud RM: Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site. Biochemistry. 1995 Dec 19;34(50):16279-87. [Article]
  14. Phan J, Koli S, Minor W, Dunlap RB, Berger SH, Lebioda L: Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug. Biochemistry. 2001 Feb 20;40(7):1897-902. [Article]
  15. Phan J, Steadman DJ, Koli S, Ding WC, Minor W, Dunlap RB, Berger SH, Lebioda L: Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors. J Biol Chem. 2001 Apr 27;276(17):14170-7. Epub 2001 Jan 24. [Article]

Associated Data

Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
Raltitrexedapproved, investigationalyestargetinhibitorDetails
FloxuridineapprovedyestargetDetails
Fluorouracilapprovedyestargetother/unknownDetails
Pemetrexedapproved, investigationalyestargetinhibitorDetails
Capecitabineapproved, investigationalyestargetinhibitorDetails
GemcitabineapprovedunknowntargetinhibitorDetails
Deoxyuridine monophosphateexperimentalunknowntargetDetails
S,S-(2-Hydroxyethyl)ThiocysteineexperimentalunknowntargetDetails
Thymidine monophosphateexperimentalunknowntargetproduct ofDetails
Trifluridineapproved, investigationalyestargetinhibitorDetails
ANX-510investigationalunknowntargetDetails
ThymectacininvestigationalunknowntargetDetails
OSI-7904LinvestigationalunknowntargetDetails
10-Propargyl-5,8-Dideazafolic AcidexperimentalunknowntargetDetails
2,4-Diamino-5-phenyl-6-ethylpyrimidineexperimentalunknowntargetDetails
N-[2-Chloro-5-(trifluoromethyl)phenyl]imidodicarbonimidic diamideexperimentalunknowntargetDetails
N-(3,5-dimethoxyphenyl)imidodicarbonimidic diamideexperimentalunknowntargetDetails
6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINEexperimentalunknowntargetDetails
FluorouracilapprovedunknownenzymesubstrateDetails
MethotrexateapprovedunknownenzymesubstrateDetails
Pralatrexateapproved, investigationalunknowntargetsubstrateinhibitorDetails
Tegafur-uracilapproved, investigationalyestargetantagonistDetails
Tegafurapproved, investigationalyestargetinhibitorDetails
MethotrexateapprovedyestargetinhibitorDetails
Fosifloxuridine nafalbenamideinvestigationalyestargetinhibitorDetails