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P04818 (TYSY_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 162. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Thymidylate synthase

Short name=TS
Short name=TSase
EC=2.1.1.45
Gene names
Name:TYMS
Synonyms:TS
ORF Names:OK/SW-cl.29
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length313 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Ref.13

Catalytic activity

5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP. HAMAP-Rule MF_00008

Pathway

Pyrimidine metabolism; dTTP biosynthesis. HAMAP-Rule MF_00008

Subunit structure

Homodimer.

Subcellular location

Nucleus. Cytoplasm. Mitochondrion. Mitochondrion matrix. Mitochondrion inner membrane Ref.13.

Sequence similarities

Belongs to the thymidylate synthase family.

Ontologies

Keywords
   Biological processNucleotide biosynthesis
   Cellular componentCytoplasm
Membrane
Mitochondrion
Mitochondrion inner membrane
Nucleus
   Coding sequence diversityAlternative splicing
   Molecular functionMethyltransferase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processDNA repair

Non-traceable author statement PubMed 15504738. Source: UniProtKB

DNA replication

Non-traceable author statement PubMed 15504738. Source: UniProtKB

G1/S transition of mitotic cell cycle

Traceable author statement. Source: Reactome

aging

Inferred from electronic annotation. Source: Ensembl

cartilage development

Inferred from electronic annotation. Source: Ensembl

circadian rhythm

Inferred from electronic annotation. Source: Ensembl

dTMP biosynthetic process

Inferred from electronic annotation. Source: Ensembl

dTTP biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

dUMP metabolic process

Inferred from electronic annotation. Source: Ensembl

deoxyribonucleoside monophosphate biosynthetic process

Traceable author statement Ref.1. Source: ProtInc

developmental growth

Inferred from electronic annotation. Source: Ensembl

immortalization of host cell by virus

Inferred from electronic annotation. Source: Ensembl

intestinal epithelial cell maturation

Inferred from electronic annotation. Source: Ensembl

mitotic cell cycle

Traceable author statement. Source: Reactome

nucleobase-containing compound metabolic process

Traceable author statement Ref.1. Source: ProtInc

nucleobase-containing small molecule metabolic process

Traceable author statement. Source: Reactome

organ regeneration

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol-mediated signaling

Non-traceable author statement PubMed 15504738. Source: UniProtKB

polysaccharide metabolic process

Inferred from electronic annotation. Source: Ensembl

pyrimidine nucleobase metabolic process

Traceable author statement. Source: Reactome

pyrimidine nucleoside biosynthetic process

Traceable author statement. Source: Reactome

regulation of transcription involved in G1/S transition of mitotic cell cycle

Traceable author statement. Source: Reactome

response to cytokine

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to ethanol

Inferred from electronic annotation. Source: Ensembl

response to folic acid

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from electronic annotation. Source: Ensembl

response to organophosphorus

Inferred from expression pattern PubMed 16079077. Source: UniProtKB

response to progesterone

Inferred from electronic annotation. Source: Ensembl

response to toxic substance

Inferred from electronic annotation. Source: Ensembl

response to vitamin A

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

tetrahydrofolate metabolic process

Inferred from electronic annotation. Source: Ensembl

uracil metabolic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from direct assay Ref.13. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

mitochondrial inner membrane

Inferred from direct assay Ref.13. Source: UniProtKB

mitochondrial matrix

Inferred from direct assay Ref.13. Source: UniProtKB

mitochondrion

Inferred from direct assay Ref.13. Source: UniProtKB

nucleolus

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.13. Source: UniProtKB

   Molecular_functioncofactor binding

Inferred from electronic annotation. Source: Ensembl

drug binding

Inferred from electronic annotation. Source: Ensembl

folic acid binding

Inferred from electronic annotation. Source: Ensembl

mRNA binding

Inferred from electronic annotation. Source: Ensembl

nucleotide binding

Inferred from electronic annotation. Source: Ensembl

thymidylate synthase activity

Traceable author statement. Source: Reactome

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P04818-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P04818-2)

Also known as: delta4;

The sequence of this isoform differs from the canonical sequence as follows:
     152-185: Missing.
Note: Expressed both in normal and cancerous tissues.
Isoform 3 (identifier: P04818-3)

Also known as: delta2+3;

The sequence of this isoform differs from the canonical sequence as follows:
     69-151: Missing.
Note: Expressed only in cancerous tissues.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.9 Ref.10
Chain2 – 313312Thymidylate synthase HAMAP-Rule MF_00008
PRO_0000140901

Sites

Active site1951

Amino acid modifications

Modified residue1141Phosphoserine Ref.11

Natural variations

Alternative sequence69 – 15183Missing in isoform 3.
VSP_047745
Alternative sequence152 – 18534Missing in isoform 2.
VSP_047746

Secondary structure

........................................................... 313
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 148D377F19915B6A

FASTA31335,716
        10         20         30         40         50         60 
MPVAGSELPR RPLPPAAQER DAEPRPPHGE LQYLGQIQHI LRCGVRKDDR TGTGTLSVFG 

        70         80         90        100        110        120 
MQARYSLRDE FPLLTTKRVF WKGVLEELLW FIKGSTNAKE LSSKGVKIWD ANGSRDFLDS 

       130        140        150        160        170        180 
LGFSTREEGD LGPVYGFQWR HFGAEYRDME SDYSGQGVDQ LQRVIDTIKT NPDDRRIIMC 

       190        200        210        220        230        240 
AWNPRDLPLM ALPPCHALCQ FYVVNSELSC QLYQRSGDMG LGVPFNIASY ALLTYMIAHI 

       250        260        270        280        290        300 
TGLKPGDFIH TLGDAHIYLN HIEPLKIQLQ REPRPFPKLR ILRKVEKIDD FKAEDFQIEG 

       310 
YNPHPTIKME MAV 

« Hide

Isoform 2 (delta4) [UniParc].

Checksum: 10B3A53DE10AB763
Show »

FASTA27931,759
Isoform 3 (delta2+3) [UniParc].

Checksum: D09F8316A504A02A
Show »

FASTA23026,140

References

« Hide 'large scale' references
[1]"Nucleotide sequence of a functional cDNA for human thymidylate synthase."
Takeishi K., Kaneda S., Ayusawa D., Shimizu K., Gotoh O., Seno T.
Nucleic Acids Res. 13:2035-2043(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Structural and functional analysis of the human thymidylate synthase gene."
Kaneda S., Nalbantoglu J., Takeishi K., Shimizu K., Gotoh O., Seno T., Ayusawa D.
J. Biol. Chem. 265:20277-20284(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Differential alternative splicing expressions of thymidylate synthase isoforms."
Hisatomi H., Tanemura H., Iizuka T., Katsumata K., Nagao K., Sumida H., Udagawa H., Hikiji K.
Cancer Lett. 193:127-131(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), ALTERNATIVE SPLICING.
[4]"Identification of immuno-peptidmics that are recognized by tumor-reactive CTL generated from TIL of colon cancer patients."
Shichijo S., Itoh K.
Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Colon adenocarcinoma.
[5]"DNA sequence and analysis of human chromosome 18."
Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. expand/collapse author list , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.
Nature 437:551-555(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Bone marrow, Placenta and Skin.
[8]"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."
Takeishi K., Kaneda S., Ayusawa D., Shimizu K., Gotoh O., Seno T.
J. Biochem. 106:575-583(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE OF 1-68.
[9]"Purification and NH2-terminal amino acid sequence of human thymidylate synthase in an overproducing transformant of mouse FM3A cells."
Shimizu K., Ayusawa D., Takeishi K., Seno T.
J. Biochem. 97:845-850(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-25.
[10]"Expression of human thymidylate synthase in Escherichia coli."
Davisson V.J., Sirawaraporn W., Santi D.V.
J. Biol. Chem. 264:9145-9148(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-10.
[11]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[12]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria."
Anderson D.D., Quintero C.M., Stover P.J.
Proc. Natl. Acad. Sci. U.S.A. 108:15163-15168(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]"Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site."
Schiffer C.A., Clifton I.J., Davisson V.J., Santi D.V., Stroud R.M.
Biochemistry 34:16279-16287(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
[16]"Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug."
Phan J., Koli S., Minor W., Dunlap R.B., Berger S.H., Lebioda L.
Biochemistry 40:1897-1902(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[17]"Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors."
Phan J., Steadman D.J., Koli S., Ding W.C., Minor W., Dunlap R.B., Berger S.H., Lebioda L.
J. Biol. Chem. 276:14170-14177(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
+Additional computationally mapped references.

Web resources

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X02308 mRNA. Translation: CAA26178.1.
D00596 Genomic DNA. Translation: BAA00472.1.
AB077207 mRNA. Translation: BAB83676.1.
AB077208 mRNA. Translation: BAB83677.1.
AB062290 mRNA. Translation: BAB93473.1.
AP001178 Genomic DNA. No translation available.
CH471113 Genomic DNA. Translation: EAX01716.1.
CH471113 Genomic DNA. Translation: EAX01720.1.
BC002567 mRNA. Translation: AAH02567.1.
BC013919 mRNA. Translation: AAH13919.1.
BC083512 mRNA. Translation: AAH83512.1.
D00517 Genomic DNA. Translation: BAA00404.1.
PIRYXHUT. A23047.
RefSeqNP_001062.1. NM_001071.2.
UniGeneHs.369762.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1HVYX-ray1.90A/B/C/D26-313[»]
1HW3X-ray2.00A1-313[»]
1HW4X-ray2.06A1-313[»]
1HZWX-ray2.00A/B1-313[»]
1I00X-ray2.50A/B1-313[»]
1JU6X-ray2.89A/B/C/D1-313[»]
1JUJX-ray3.00A/B/C/D1-313[»]
1YPVX-ray1.80A1-313[»]
2ONBX-ray2.70A1-313[»]
2RD8X-ray2.50A/B1-313[»]
2RDAX-ray2.67A/B/C/D/E/F1-313[»]
3EAWX-ray1.86X1-313[»]
3EBUX-ray2.05A1-313[»]
3ED7X-ray1.56A21-313[»]
3EDWX-ray1.75X1-313[»]
3EF9X-ray3.20A1-313[»]
3EGYX-ray2.18X1-313[»]
3EHIX-ray2.00X1-313[»]
3EJLX-ray3.20A/B/C/D1-313[»]
3GG5X-ray2.77A/B/C/D1-313[»]
3GH0X-ray1.56A1-313[»]
3GH2X-ray1.75X1-313[»]
3H9KX-ray2.65A/B/C/D/E1-313[»]
3HB8X-ray2.74A/B/C/D/E1-313[»]
3N5EX-ray2.26A/B1-313[»]
3N5GX-ray2.27A1-313[»]
3OB7X-ray2.75A/B/C/D/E1-313[»]
4E28X-ray2.30A1-313[»]
4FGTX-ray2.00A1-311[»]
4G2OX-ray2.25X1-313[»]
4G6WX-ray2.30X1-313[»]
4GD7X-ray2.29A1-313[»]
4GYHX-ray3.00A1-313[»]
4H1IX-ray3.10A/B/C/D1-313[»]
DisProtDP00073.
ProteinModelPortalP04818.
SMRP04818. Positions 1-313.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid113149. 37 interactions.
IntActP04818. 2 interactions.
MINTMINT-2800458.
STRING9606.ENSP00000315644.

Chemistry

BindingDBP04818.
ChEMBLCHEMBL1952.
DrugBankDB01101. Capecitabine.
DB00322. Floxuridine.
DB00544. Fluorouracil.
DB00441. Gemcitabine.
DB00650. Leucovorin.
DB00642. Pemetrexed.
DB00293. Raltitrexed.
DB00432. Trifluridine.
GuidetoPHARMACOLOGY2642.

PTM databases

PhosphoSiteP04818.

Polymorphism databases

DMDM136611.

Proteomic databases

PaxDbP04818.
PRIDEP04818.

Protocols and materials databases

DNASU7298.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000323224; ENSP00000314727; ENSG00000176890. [P04818-2]
ENST00000323250; ENSP00000314902; ENSG00000176890. [P04818-3]
ENST00000323274; ENSP00000315644; ENSG00000176890. [P04818-1]
GeneID7298.
KEGGhsa:7298.
UCSCuc010dka.1. human. [P04818-1]

Organism-specific databases

CTD7298.
GeneCardsGC18P000657.
HGNCHGNC:12441. TYMS.
HPACAB002784.
MIM188350. gene.
neXtProtNX_P04818.
Orphanet240839. 5-fluorouracil toxicity.
240855. Capecitabine toxicity.
240955. Susceptibility to adverse reaction due to 5-fluorouracil treatment.
240963. Susceptibility to adverse reaction due to capecitabine treatment.
PharmGKBPA359.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0207.
HOGENOMHOG000257899.
HOVERGENHBG001934.
InParanoidP04818.
KOK00560.
OMANLGPVYG.
OrthoDBEOG725DHX.
PhylomeDBP04818.
TreeFamTF353027.

Enzyme and pathway databases

BioCycMetaCyc:HS11096-MONOMER.
ReactomeREACT_111217. Metabolism.
REACT_115566. Cell Cycle.
SABIO-RKP04818.
UniPathwayUPA00575.

Gene expression databases

ArrayExpressP04818.
BgeeP04818.
CleanExHS_TYMS.
GenevestigatorP04818.

Family and domain databases

Gene3D3.30.572.10. 1 hit.
HAMAPMF_00008. Thymidy_synth_bact.
InterProIPR023451. Thymidate_synth/dCMP_Mease.
IPR000398. Thymidylate_synthase.
IPR020940. Thymidylate_synthase_AS.
[Graphical view]
PfamPF00303. Thymidylat_synt. 1 hit.
[Graphical view]
PRINTSPR00108. THYMDSNTHASE.
SUPFAMSSF55831. SSF55831. 1 hit.
TIGRFAMsTIGR03284. thym_sym. 1 hit.
PROSITEPS00091. THYMIDYLATE_SYNTHASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSTYMS. human.
EvolutionaryTraceP04818.
GeneWikiThymidylate_synthase.
GenomeRNAi7298.
NextBio28543.
PROP04818.
SOURCESearch...

Entry information

Entry nameTYSY_HUMAN
AccessionPrimary (citable) accession number: P04818
Secondary accession number(s): Q8WYK3, Q8WYK4
Entry history
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 162 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 18

Human chromosome 18: entries, gene names and cross-references to MIM