thymidylate synthase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/10/05 14:54:26」(JST)

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TYMS
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1YPV, 1JU6, 2RDA, 3EF9, 3ED7, 1HW3, 3EHI, 3GH0, 4JEF, 4O1X, 1HZW, 3EAW, 3OB7, 3EBU, 4KPW, 3EGY, 3EJL, 3N5G, 3N5E, 1HVY, 4GD7, 4G2O, 4H1I, 2ONB, 3H9K, 4GYH, 3HB8, 1I00, 3GG5, 4FGT, 2RD8, 3EDW, 4G6W, 1HW4, 3GH2, 4E28, 1JUJ, 4O1U, 4UP1, 5HS3,%%s1HW3, 1YPV, 4GD7, 2ONB
Identifiers
Aliases	TYMS, HST422, TMS, TS, thymidylate synthetase
External IDs	OMIM: 188350 MGI: 98878 HomoloGene: 834 GeneCards: TYMS
Gene location (Human) Chr. Chromosome 18 (human) Band 18p11.32 Start 657,604 bp End 673,578 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5 B1|5 15.81 cM Start 30,058,202 bp End 30,073,617 bp
RNA expression pattern More reference expression data
Gene ontology Molecular function • methyltransferase activity • transferase activity • nucleotide binding • protein homodimerization activity • folic acid binding • thymidylate synthase activity • drug binding • cofactor binding • mRNA binding • translation repressor activity, nucleic acid binding • sequence-specific mRNA binding Cellular component • cytoplasm • cytosol • membrane • mitochondrial matrix • nucleolus • mitochondrion • mitochondrial inner membrane • nucleus Biological process • response to cytokine • nucleotide biosynthetic process • DNA biosynthetic process • response to organic cyclic compound • response to progesterone • tetrahydrofolate interconversion • aging • response to glucocorticoid • immortalization of host cell by virus • regulation of transcription involved in G1/S transition of mitotic cell cycle • dTTP biosynthetic process • tetrahydrofolate metabolic process • response to vitamin A • cell growth • cartilage development • methylation • developmental growth • response to organophosphorus • circadian rhythm • uracil metabolic process • dTMP biosynthetic process • intestinal epithelial cell maturation • dUMP metabolic process • response to folic acid • response to ethanol • cell proliferation • response to toxic substance • response to drug • pyrimidine nucleobase metabolic process • regulation of translation • liver regeneration • nucleobase-containing small molecule interconversion • negative regulation of translation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7298	22171
Ensembl	ENSG00000176890	ENSMUSG00000025747
UniProt	P04818 Q53Y97	P07607
RefSeq (mRNA)	NM_001071 NM_001354867 NM_001354868	NM_021288
RefSeq (protein)	NP_001062 NP_001341796 NP_001341797 NP_001062.1	NP_067263
Location (UCSC)	Chr 18: 0.66 – 0.67 Mb	Chr 18: 30.06 – 30.07 Mb
PubMed search
Wikidata
View/Edit Human View/Edit Mouse

thymidylate synthase
Identifiers
EC number	2.1.1.45
CAS number	9031-61-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Thymidylate synthase
Identifiers
Symbol	Thymidylat_synt
Pfam	PF00303
InterPro	IPR000398
PROSITE	PDOC00086
SCOP	1tys
SUPERFAMILY	1tys
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Thymidylate synthetase (EC 2.1.1.45) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

Function

The following reaction is catalyzed by thymidylate synthetase:

5,10-methylenetetrahydrofolate + dUMP $\rightleftharpoons$ dihydrofolate + dTMP

By means of reductive methylation, deoxyuridine monophosphate (dUMP) and N5,N10-methylene tetrahydrofolate are together used to form dTMP, yielding dihydrofolate as a secondary product.

This provides the sole de novo pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer. The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process cause various biological and genetic abnormalities, such as thymineless death. The enzyme is an important target for certain chemotherapeutic drugs. Thymidylate synthase is an enzyme of about 30 to 35 kDa in most species except in protozoan and plants where it exists as a bifunctional enzyme that includes a dihydrofolate reductase domain. A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate). The sequence around the active site of this enzyme is conserved from phages to vertebrates.

Thymidylate synthase is induced by a transcription factor LSF/TFCP2 and LSF is an oncogene in hepatocellular carcinoma. LSF and Thymidylate synthase plays significant role in Liver Cancer proliferation and progression and Drug resistance.

Clinical significance

Thymidylate synthase (TS) plays a crucial role in the early stages of DNA biosynthesis. DNA damage or deletion occur on a daily basis as a result of both endogenous and environmental factors. Such environmental factors include ultraviolet damage and cigarette smoke that contain a variety of carcinogens. Therefore, synthesis and insertion of healthy DNA is vital for normal body functions and avoidance of cancerous activity. In addition, inhibition in synthesis of important nucleotides necessary for cell growth is important. For this reason, TS has become an important target for cancer treatment by means of chemotherapy. The sensitivity of TS to succumb to TS inhibitors is a key part to its success as treatment for colorectal, pancreatic, ovarian, gastric, and breast cancers.

Using TS as a drug target

The use of TS inhibitors has become a main focus of using TS as a drug target. The most widely used inhibitor is 5-fluorouracil (5-FU), which acts as an antimetabolite that irreversibly inhibits TS by competitive binding. However, due to a low level of 5-FU found in many patients, it has been discovered that in combination with leucovorin (LV), 5-FU has greater success in down regulating tumor progression mechanisms and increasing immune system activity.

Experimentally, it has been shown that low levels of TS expression leads to a better response to 5-FU and higher success rates and survival of colon and liver cancer patients. However, additional experiments have merely stated that levels of TS may be associated with stage of disease, cell proliferation and tumor differentiation for those with lung adenocarcinoma but low levels are not necessarily indicators of high success. Expression levels of TS mRNA may be helpful in predicting the malignant potential of certain cancerous cells, thus improving cancer treatment targets and yielding higher survival rates among cancer patients [Hashimoto].

TS’s relation to the cell cycle also contributes to its use in cancer treatment. Several cell-cycle dependent kinases and transcription factors influence TS levels in the cell cycle that increase its activity during the S phase but decrease its activity while cells are no longer proliferating. In an auto-regulatory manner, TS not only controls its own translation but that of other proteins such as p53 that through mutation is the root of much tumor growth. Through its translation, TS has a varying expression in cancer cells and tumors, which leads to early cell death.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|{{{bSize}}}px|alt=Fluorouracil (5-FU) Activity edit]]

File:FluoropyrimidineActivity_WP1601.png

Fluorouracil (5-FU) Activity edit

Mechanism description

This shows the overall pathway that thymidylate synthase and its intermediates take

In the proposed mechanism, TS forms a covalent bond to the substrate dUMP through a 1,4-addition involving a cysteine nucleophile. The coenzyme tetrahydrofolate donates a methyl group to the alpha carbon while reducing the new methyl on dUMP to form dTMP.

This shows the intricate interactions of the UMP in the active site of thymidylate synthase.

It has been proven that the imine formed through reaction with THF and dUMP is an intermediate in the reaction with dUMP through mutations in the structure of TS that inhibit the completion of the mechanism. V316Am TS, a mutant with deletion of C terminal valines from both subunits, allows the catalysis of dehalogenation of BrdUMP preceding the mechanism described above and the covalent bond to THF and dUMP. The mutant TS is unable to accomplish the C-terminal conformational change needed to break covalent bonds to form dTMP, thus showing the proposed mechanism to be true. The structure was deduced through x-ray crystallography of V316Am TS to illustrate full homodimer TS structure (Figure 1). In addition, it showed possible interactions of the 175Arg and 174Arg between dimers. These arginines are thought to stabilize the UMP structures within the active sites by creating hydrogen bonds to the phosphate group (Figure 2). [Stroud and Finer-Moore] 5-FU is an inhibitor of TS. Upon entering the cell, 5-fluorouracil (5-FU) is converted to a variety of active metabolites, intracellularly. One such metabolite is FdUMP which differs from dUMP by a fluorine in place of a hydrogen on the alpha carbon. FdUMP is able to inhibit TS by binding to the nucleotide-binding site of dUMP. This competitive binding inhibits the normal function of dTMP synthesis from dUMP [Longley]. Thus the dUMP is unable to have an elimination reaction and complete the methyl donation from THF.

Thymidylate synthase as a homodimer

Figure 1. This figure depicts the homodimer that is TS. As you can see the orange and teal backbones never connect or intertwine, but there are side chains interactions between the dimers. On the orange protein, you can visibly detect two long side chains that enter the teal protein (this is located within the yellow circle). The other beige parts are side chains that interact within the active site. Just below the yellow circle, you are able to see the same pattern of side chains and configuration.

Active site of Thymidylate Synthase

Figure 2. This figure shows the possible H-bond interactions between the arginines and the UMP in the active site of thymidylate synthase. This can be seen by the faint lines between the blue tips and the red tips. These arginines are used to hold the position of the UMP molecule so that the interaction may occur correctly. The two arginines in the top right corner that are located next to each other on the back bone are actually from the other protein of this dimer enzyme. This interaction is one of the many intermolecular forces that holds these two tertiary structures together. The yellow stand in the top-middle region shows a sulfur bond that forms between a cysteine side chain and UMP. This covalently holds the UMP within the active site until it is reacted to yield TMP.

See also

• Pyrimidine analogues
• Thymidylate synthase inhibitor
• Thymidine kinase
• Thymidine kinase in clinical chemistry
• Thymidylate kinase

Further reading

• Carreras CW, Santi DV (1995). "The Catalytic Mechanism and Structure of Thymidylate Synthase". Annual Review of Biochemistry. 64 (1): 721–762. PMID 7574499. doi:10.1146/annurev.bi.64.070195.003445. 
• Banerjee D, Mayer-Kuckuk P, Capiaux G, et al. (2002). "Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase". Biochim. Biophys. Acta. 1587 (2–3): 164–73. PMID 12084458. doi:10.1016/S0925-4439(02)00079-0. 
• Liu J, Schmitz JC, Lin X, et al. (2002). "Thymidylate synthase as a translational regulator of cellular gene expression". Biochim. Biophys. Acta. 1587 (2–3): 174–82. PMID 12084459. doi:10.1016/s0925-4439(02)00080-7. 
• Chu J, Dolnick BJ (2002). "Natural antisense (rTSalpha) RNA induces site-specific cleavage of thymidylate synthase mRNA". Biochim. Biophys. Acta. 1587 (2–3): 183–93. PMID 12084460. doi:10.1016/s0925-4439(02)00081-9. 
• Peters GJ, Backus HH, Freemantle S, et al. (2002). "Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism". Biochim. Biophys. Acta. 1587 (2–3): 194–205. PMID 12084461. doi:10.1016/S0925-4439(02)00082-0. 
• Costi MP, Tondi D, Rinaldi M, et al. (2002). "Structure-based studies on species-specific inhibition of thymidylate synthase". Biochim. Biophys. Acta. 1587 (2–3): 206–14. PMID 12084462. doi:10.1016/s0925-4439(02)00083-2. 
• Lin D, Li H, Tan W, et al. (2007). "Genetic polymorphisms in folate- metabolizing enzymes and risk of gastroesophageal cancers: a potential nutrient-gene interaction in cancer development". Forum of nutrition. Forum of Nutrition. 60: 140–5. ISBN 3-8055-8216-1. PMID 17684410. doi:10.1159/000107090. 

External links

• Thymidylate synthetase at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 成人における抗癌剤の投与 dosing of anticancer agents in adults
• 2. 大腸癌の病理および予後決定因子 pathology and prognostic determinants of colorectal cancer
• 3. 化学療法剤の腸管毒性 enterotoxicity of chemotherapeutic agents
• 4. Management of acute chemotherapy-related diarrhea
• 5. 転移性大腸癌に対する全身化学療法：終了した臨床試験 systemic chemotherapy for metastatic colorectal cancer completed clinical trials

English Journal

• Increased risk of severe fluoropyrimidine-associated toxicity in patients carrying a G to C substitution in the first 28-bp tandem repeat of the thymidylate synthase 2R allele.

• Meulendijks D1,2, Jacobs BA1,2, Aliev A2, Pluim D2, van Werkhoven E3, Deenen MJ4, Beijnen JH5,6, Cats A7, Schellens JH1,2,6.
• International journal of cancer. Journal international du cancer.Int J Cancer.2016 Jan 1;138(1):245-53. doi: 10.1002/ijc.29694. Epub 2015 Oct 1.
• The fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5'-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer reg
• PMID 26189437

• A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

• Grem JL1, Kos ME2, Evande RE1, Meza JL3, Schwarz JK1.
• Cancer.Cancer.2015 Nov 1;121(21):3862-8. doi: 10.1002/cncr.29504. Epub 2015 Aug 4.
• BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluo
• PMID 26242208

Japanese Journal

• Effect of dUMP Halogen Substitutions to Non-Covalent Ternary Complex Stability and Michael Addition Reactivity in Thymidylate Synthase/dUMP/mTHF Complex : Molecular Dynamics and Abinitio quantum Mechanics/Molecular Mechanics Techniques

• 旭硝子財団助成研究成果報告 Reports of research assisted by the Asahi Glass Foundation, 1-13, 2015
• NAID 40020615254

• Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage Ⅱ/Ⅲ gastric cancer

• Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 18(3), 538-549, 2015
• NAID 40020581308

Related Links

• Monoclonal Mouse Anti-Human Thymidylate Synthase ...

Thymidylate Synthase（TS，チミジル酸合成酵素）は DNA 合成において重要な酵素であり、DNA 生合成に必要なチミンヌクレオチドを生成するために 5,10-methylenetetrahydrofolate（CH2THF，活性型葉酸）と共に dUMP をメチル化し ...

• Thymidylate synthaseとは - goo Wikipedia (ウィキペディア)

Figure 2. This figure shows the possible H-bond interactions between the arginines and the UMP in the active site of thymidylate synthase. This can be seen by the faint lines between the blue tips and the red tips. These arginines are ...

Related Pictures

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★リンクテーブル★

リンク元	「チミジル酸シンターゼ」
関連記事	「synthase」「thymidylate」

「チミジル酸シンターゼ」

　　[★]

英

thymidylate synthase

同

チミジル酸合成酵素

関

チミン、dTMP

「synthase」

　　[★]

• n.

• (脱離酵素リアーゼの逆反応である合成方向の反応を指す) シンターゼ, 合成酵素, 付加酵素

関

lyase、synthetase、transferase

「thymidylate」

　　[★]

チミジル酸、チミジン一リン酸

関

deoxythymidine monophosphate、dTMP、thymidine monophosphate、thymidylic acid