2.1.1.45: thymidylate synthase
This is an abbreviated version!
For detailed information about thymidylate synthase, go to the full flat file.
Word Map on EC 2.1.1.45
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2.1.1.45
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5-fluorouracil
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thymidine
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colorectal
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dihydrofolate
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antifolate
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methotrexate
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dihydropyrimidine
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pyrimidine
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fluoropyrimidine
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phosphorylase
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ribonucleotide
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leucovorin
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pemetrexed
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resect
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fdump
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uracil
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mthfr
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casey
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schedule
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polyglutamates
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non-small
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cisplatin
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folylpolyglutamate
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deoxyuridine
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oxaliplatin
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5-fluoro-2'-deoxyuridine
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antimetabolite
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orotate
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irinotecan
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capecitabine
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5-fu-based
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ccrf-cem
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folate-dependent
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gemcitabine
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folinic
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formyltransferase
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quinazoline
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glycinamide
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dttp
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polyglutamylation
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2'-deoxyuridine
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tegafur
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medicine
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methotrexate-resistant
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deoxycytidylate
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cross-complementing
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drug development
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transformylase
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5-fu-induced
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dutpase
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aminopterin
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deoxythymidine
- 2.1.1.45
- 5-fluorouracil
- thymidine
- colorectal
- dihydrofolate
- antifolate
- methotrexate
- dihydropyrimidine
- pyrimidine
-
fluoropyrimidine
- phosphorylase
- ribonucleotide
- leucovorin
- pemetrexed
-
resect
- fdump
- uracil
- mthfr
-
casey
-
schedule
- polyglutamates
-
non-small
- cisplatin
- folylpolyglutamate
- deoxyuridine
- oxaliplatin
- 5-fluoro-2'-deoxyuridine
-
antimetabolite
- orotate
- irinotecan
- capecitabine
-
5-fu-based
-
ccrf-cem
-
folate-dependent
- gemcitabine
-
folinic
-
formyltransferase
- quinazoline
- glycinamide
- dttp
-
polyglutamylation
- 2'-deoxyuridine
-
tegafur
- medicine
-
methotrexate-resistant
- deoxycytidylate
-
cross-complementing
- drug development
-
transformylase
-
5-fu-induced
- dutpase
- aminopterin
- deoxythymidine
Reaction
Synonyms
BgDHFR-TS, bifunctional TS-DHFR, DFR-TS, DHFR-TS, DHFR–TS, dihydrofolate reductase-thymidylate synthase, dTMP synthase, HTS, human TS, LBRM_06_0830, methylenetetrahydrofolate:dUMP C-methyltransferase, More, Thy1, ThyA, thymidylate synthase, thymidylate synthase A, thymidylate synthase-dihydrofolate reductase, thymidylate synthetase, ThyX, TMP synthetase, TMPS, TS, TS-DHFR, TSase, TYMS, Y110A7A.4
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General Information
General Information on EC 2.1.1.45 - thymidylate synthase
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evolution
malfunction
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growth of single-knockout lines of dihydrofolate reductase-thymidylate synthase in vitro are identical to wild type cells, whereas double-knockout lines of dihydrofolate reductase-thymidylate synthase have an absolute requirement for thymidine
metabolism
physiological function
additional information
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
evolution
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
evolution
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
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ThyA is the sole catalyst for thymidylate biosynthesis in Corynebacterium glutamicum
metabolism
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ThyA is the sole catalyst for thymidylate biosynthesis in Corynebacterium glutamicum
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physiological function
thymidylate synthase is the only de novo source of dTMP and is essential for DNA replication
physiological function
thymidylate synthase is the only de novo source of dTMP and is essential for DNA replication
physiological function
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thymidylate synthase plays an essential role in embryogenesis, embryos with their thymidylate synthase function inhibited show a retarded embryo development and irregular cell sizes
physiological function
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the enzyme is essential for the de novo synthesis of DNA
physiological function
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the enzyme is indispensable for DNA replication in actively dividing cells
physiological function
DHFR-TS is essential for cell survival of Trypanosoma brucei
physiological function
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain in contrast to the human enzyme. Three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, shows that the TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions
physiological function
the human thymidylate synthase and dihydrofolate reductase catalyse two consecutive reactions in the folate metabolism pathway and are very likely to bind in the same multi-enzyme complex in vivo, substrate channeling occurs between the human thymidylate synthase and dihydrofolate reductase, analysis by protein-protein docking, electrostatics calculations, and Brownian dynamics, overview. The non-covalently bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface electrostatic highway. The substrate channeling efficiency between the two can be reasonably high and comparable to that of the bifunctional protozoan enzyme
physiological function
human thymidylate synthase and dihydrofolate reductase form a strong complex in vitro and colocalize in human normal and colon cancer cell cytoplasm and nucleus. Treatment of cancer cells with methotrexate or 5-fluorouracil does not affect the distribution of either enzyme within the cells. 5-fluorouracil, but not methotrexate, lowers the presence of dihydrofolate reductase-thymidylate synthase complex in the nucleus by 2.5fold
physiological function
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the nucleotide binds to the free and singly bound forms of the enzyme with nearly equal affinity over a broad range of temperatures and in multiple buffers. There are small but significant differences in DELTACP for the two binding event, so the active sites are not formally equivalent. There is little-to-no allostery at the level of DELTAGbind. There is minor inter-subunit cooperativity in formation of a ternary complex with the mechanism-based inhibitor, 5F-dUMP, and cofactor
physiological function
two insert regions in thymidylate synthase, the functions of which are unclear, are involved in the conformational transition between the active and inactive state. A cavity in the dimer interface could serve as an allosteric site to regulate the conformational switching between the active and inactive states
physiological function
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thymidylate synthase plays an essential role in embryogenesis, embryos with their thymidylate synthase function inhibited show a retarded embryo development and irregular cell sizes
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physiological function
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DHFR-TS is essential for cell survival of Trypanosoma brucei
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in vitro, one human thymidylate synthase dimer binds to up to six human dihydrofolate reductase monomers, protein-protein docking process, overview. Existence of bound-state conformations of the human DHFR and TS proteins where a continuous positive surface potential region, connecting the TS and DHFR active sites, is formed
additional information
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in vitro, one human thymidylate synthase dimer binds to up to six human dihydrofolate reductase monomers, protein-protein docking process, overview. Existence of bound-state conformations of the human DHFR and TS proteins where a continuous positive surface potential region, connecting the TS and DHFR active sites, is formed
additional information
TS domain structure analysis, overview. The TS domain of the enzyme forms the largest portion of the dimerization interface mainly through a five-stranded beta-sheet from each monomer. The catalytic cysteine 489 is responsible for catalysis, te active site is comprised of residues from both monomers. Several conserved arginines bind dUMP, i.e. R344, R510 as well as R469 and R470 from the adjacent monomer
additional information
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TS domain structure analysis, overview. The TS domain of the enzyme forms the largest portion of the dimerization interface mainly through a five-stranded beta-sheet from each monomer. The catalytic cysteine 489 is responsible for catalysis, te active site is comprised of residues from both monomers. Several conserved arginines bind dUMP, i.e. R344, R510 as well as R469 and R470 from the adjacent monomer