P04818 (TYSY_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	313 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Ref.9
Catalytic activity	5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP.
Pathway	Pyrimidine metabolism; dTTP biosynthesis.
Subunit structure	Homodimer.
Subcellular location	Nucleus. Cytoplasm. Mitochondrion. Mitochondrion matrix. Mitochondrion inner membrane Ref.9.
Sequence similarities	Belongs to the thymidylate synthase family.

Ontologies

Keywords
Biological process	Nucleotide biosynthesis
Cellular component	Cytoplasm Membrane Mitochondrion Mitochondrion inner membrane Nucleus
Molecular function	Methyltransferase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	DNA repair Non-traceable author statement. Source: UniProtKB DNA replication Non-traceable author statement. Source: UniProtKB phosphatidylinositol-mediated signaling Non-traceable author statement. Source: UniProtKB pyrimidine base metabolic process Traceable author statement. Source: Reactome pyrimidine nucleoside biosynthetic process Traceable author statement. Source: Reactome regulation of transcription involved in G1/S phase of mitotic cell cycle Traceable author statement. Source: Reactome response to organophosphorus Inferred from expression pattern. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: Reactome mitochondrial inner membrane Inferred from direct assay Ref.9. Source: UniProtKB mitochondrial matrix Inferred from direct assay Ref.9. Source: UniProtKB nucleoplasm Traceable author statement. Source: Reactome
Molecular function	thymidylate synthase activity Traceable author statement. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.6 Ref.7

Chain

2 – 313

312

Thymidylate synthase

PRO_0000140901

Sites

Active site

195

1

Amino acid modifications

Modified residue

114

1

Phosphoserine Ref.8

Secondary structure

1

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313

Helix Strand Turn

Details...

Helix

30 – 43

14

Beta strand

45 – 47

3

Beta strand

55 – 66

12

Turn

75 – 78

4

Helix

81 – 92

12

Helix

98 – 102

5

Turn

103 – 105

3

Helix

111 – 113

3

Helix

115 – 120

6

Helix

135 – 141

7

Helix

160 – 170

11

Beta strand

178 – 180

3

Turn

184 – 186

3

Helix

187 – 189

3

Beta strand

195 – 204

10

Beta strand

207 – 218

12

Turn

219 – 221

3

Helix

222 – 240

19

Beta strand

244 – 258

15

Helix

259 – 261

3

Helix

262 – 269

8

Beta strand

278 – 281

4

Helix

288 – 290

3

Helix

293 – 295

3

Beta strand

296 – 300

5

Sequences

	Sequence		Length	Mass (Da)
	P04818 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 148D377F19915B6A	FASTA	313	35,716
	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

References

	« Hide 'large scale' referencesShow '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: 2987839] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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: 2243092] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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]. Tissue: Colon adenocarcinoma.
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow, Placenta and Skin.
[5]	"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: 2532645] [Abstract] Cited for: NUCLEOTIDE SEQUENCE OF 1-68.
[6]	"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: 3839505] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-25.
[7]	"Expression of human thymidylate synthase in Escherichia coli." Davisson V.J., Sirawaraporn W., Santi D.V. J. Biol. Chem. 264:9145-9148(1989) [PubMed: 2656695] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-10.
[8]	"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: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[9]	"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: 21876188] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"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: 8845352] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
[12]	"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: 11329255] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[13]	"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: 11278511] [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.
AB062290 mRNA. Translation: BAB93473.1.
BC002567 mRNA. Translation: AAH02567.1.
BC013919 mRNA. Translation: AAH13919.1.
BC083512 mRNA. Translation: AAH83512.1.
D00517 Genomic DNA. Translation: BAA00404.1.

IPI

IPI00221108.

PIR

YXHUT. A23047.

RefSeq

NP_001062.1. NM_001071.2.

UniGene

Hs.592338.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HVY	X-ray	1.90	A/B/C/D	26-313	[»]
1HW3	X-ray	2.00	A	1-313	[»]
1HW4	X-ray	2.06	A	1-313	[»]
1HZW	X-ray	2.00	A/B	30-313	[»]
1I00	X-ray	2.50	A/B	30-313	[»]
1JU6	X-ray	2.89	A/B/C/D	1-313	[»]
1JUJ	X-ray	3.00	A/B/C/D	1-313	[»]
1YPV	X-ray	1.80	A	1-313	[»]
2ONB	X-ray	2.70	A	1-313	[»]
2RD8	X-ray	2.50	A/B	1-313	[»]
2RDA	X-ray	2.67	A/B/C/D/E/F	1-313	[»]
3EAW	X-ray	1.86	X	1-313	[»]
3EBU	X-ray	2.05	A	1-313	[»]
3ED7	X-ray	1.56	A	26-313	[»]
3EDW	X-ray	1.75	X	1-313	[»]
3EF9	X-ray	3.20	A	1-313	[»]
3EGY	X-ray	2.18	X	1-313	[»]
3EHI	X-ray	2.00	X	1-313	[»]
3EJL	X-ray	3.20	A/B/C/D	1-313	[»]
3GG5	X-ray	2.77	A/B/C/D	1-313	[»]
3GH0	X-ray	1.56	A	1-313	[»]
3GH2	X-ray	1.75	X	1-313	[»]
3H9K	X-ray	2.65	A/B/C/D/E	1-313	[»]
3HB8	X-ray	2.74	A/B/C/D/E	1-313	[»]
3N5E	X-ray	2.26	A/B	1-313	[»]
3N5G	X-ray	2.27	A	1-313	[»]
3OB7	X-ray	2.75	A/B/C/D/E	1-313	[»]

ProteinModelPortal

P04818.

SMR

P04818. Positions 26-313.

DisProt

DP00073.

ModBase

Search...

Protein-protein interaction databases

STRING

P04818.

PTM databases

PhosphoSite

P04818.

Polymorphism databases

DMDM

136611.

Proteomic databases

PRIDE

P04818.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000323274; ENSP00000315644; ENSG00000176890.

GeneID

7298.

KEGG

hsa:7298.

UCSC

uc010dka.1. human.

Organism-specific databases

CTD

7298.

GeneCards

GC18P000647.

H-InvDB

HIX0017793.

HGNC

HGNC:12441. TYMS.

HPA

CAB002784.

MIM

188350. gene.

neXtProt

NX_P04818.

Orphanet

240839. 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.

PharmGKB

PA359.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG06875.

HOGENOM

HBG588098.

HOVERGEN

HBG001934.

InParanoid

P04818.

OMA

ANGSREF.

OrthoDB

EOG4ZKJMP.

PhylomeDB

P04818.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.
REACT_152. Cell Cycle, Mitotic.

Gene expression databases

ArrayExpress

P04818.

Bgee

P04818.

CleanEx

HS_TYMS.

Genevestigator

P04818.

GermOnline

ENSG00000176890. Homo sapiens.

Family and domain databases

InterPro

IPR023451. Thymidate_synth/dCMP_Mease.
IPR000398. Thymidylate_synthase.
IPR020940. Thymidylate_synthase_AS.
[Graphical view]

Gene3D

G3DSA:3.30.572.10. Thymidylat_synth_C. 1 hit.

KO

K00560.

Pfam

PF00303. Thymidylat_synt. 1 hit.
[Graphical view]

PRINTS

PR00108. THYMDSNTHASE.

SUPFAM

SSF55831. Thymidylat_synth_C. 1 hit.

TIGRFAMs

TIGR03284. Thym_sym. 1 hit.

PROSITE

PS00091. THYMIDYLATE_SYNTHASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P04818.

DrugBank

DB01101. Capecitabine.
DB00322. Floxuridine.
DB00544. Fluorouracil.
DB00441. Gemcitabine.
DB00650. Leucovorin.
DB00642. Pemetrexed.
DB00293. Raltitrexed.
DB00432. Trifluridine.

NextBio

28543.

SOURCE

Search...

Entry information

Entry name

TYSY_HUMAN

Accession

Primary (citable) accession number: P04818

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	January 23, 2007
Last modified:	December 14, 2011
This is version 138 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.