Thymidylate synthase

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 mitochondrial and nuclear de novo thymidylate biosynthesis pathway.

Classification

Family (Pfam)

PF00303 Thymidylat_synt

InterPro

Thymidate_synth/dCMP_Mease, Thymidate_synth/dCMP_Mease_dom, Thymidate_synth/dCMP_Mease_sf, Thymidylate_synthase, Thymidylate_synthase_AS

Functional cluster

M20 Family Metallopeptidases

Experimental structures · PDB · 61

• 1HVY X-ray 1.90A
• 1HW3 X-ray 2.00A
• 1HW4 X-ray 2.06A
• 1HZW X-ray 2.00A
• 1I00 X-ray 2.50A
• 1JU6 X-ray 2.89A
• 1JUJ X-ray 3.00A
• 1YPV X-ray 1.80A
• 2ONB X-ray 2.70A
• 2RD8 X-ray 2.50A
• 2RDA X-ray 2.67A
• 3EAW X-ray 1.86A
• … and 49 more

A predicted model is available from AlphaFold.

Gene Ontology · 19

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005743 mitochondrial inner membrane
• GO:0005759 mitochondrial matrix
• GO:0005739 mitochondrion
• GO:0005634 nucleus
• GO:0005657 replication fork
• GO:0005542 folic acid binding
• GO:0000900 mRNA regulatory element binding translation repressor activity
• GO:1990825 sequence-specific mRNA binding
• GO:0004799 thymidylate synthase activity
• GO:0006207 'de novo' pyrimidine nucleobase biosynthetic process
• GO:0071897 DNA biosynthetic process
• GO:0006260 DNA replication
• GO:0006231 dTMP biosynthetic process
• GO:0006235 dTTP biosynthetic process
• GO:0032259 methylation
• GO:0017148 negative regulation of translation
• GO:0035999 tetrahydrofolate interconversion

Disease associations

• dyskeratosis congenita, digenic MONDO:0031057

Drugs targeting this protein · 11

• DOXIFLURIDINE inhibitor
• OSI-7904 inhibitor
• CAPECITABINE inhibitor
• FLUOROURACIL inhibitor
• TEGAFUR inhibitor
• RALTITREXED inhibitor
• PEMETREXED inhibitor
• PEMETREXED DISODIUM inhibitor
• NOLATREXED antagonist
• PEMETREXED MONOHYDRATE inhibitor
• FLOXURIDINE inhibitor

Related proteins · sequence + function similarity

• Thymidylate synthase 0.96
• Thymidylate synthase 0.96
• Thymidylate synthase 0.92
• Thymidylate synthase 1/2 0.91
• Thymidylate synthase 0.91
• Thymidylate synthase 3 0.91
• Thymidylate synthase 0.90
• Thymidylate synthase 0.90
• Thymidylate synthase 0.90
• Thymidylate synthase 0.90
• Thymidylate synthase 0.90
• Thymidylate synthase 0.90

Co-cited proteins · studied together in the literature

• Dihydrofolate reductase 3 shared papers
• Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial 1 shared papers
• Mitochondrial enolase superfamily member 1 1 shared papers
• Serine hydroxymethyltransferase, cytosolic 1 shared papers
• Dihydrofolate reductase 2, mitochondrial 1 shared papers
• Serine hydroxymethyltransferase, mitochondrial 1 shared papers
• SUMO-conjugating enzyme UBC9 1 shared papers

Literature · 20 cited papers

• Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita. Am. J. Hum. Genet. · 2022
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. U.S.A. · 2012
• Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. J. Biol. Chem. · 2012
• Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc. Natl. Acad. Sci. U.S.A. · 2011
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
• Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase. Clin. Chem. Lab. Med. · 2007
• DNA sequence and analysis of human chromosome 18. Nature · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Differential alternative splicing expressions of thymidylate synthase isoforms. Cancer Lett. · 2003
• … and 8 more in the literature graph