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
ECTree
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Engineering
Engineering on EC 2.1.1.45 - thymidylate synthase
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K48Q
A17T/D116A/D254E
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the mutant shows decreased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
A191K
D254N
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the mutant shows increased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
E30W
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the mutant shows 100times lower specific activity with respect to the wild type enzyme and is resistant to 5-fluoro-2'-deoxyuridine-5'-monophosphate (6fold higher inhibition constant than the wild type enzyme)
G52S
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the mutant shows increased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
L198P
the mutant enzyme displays a kcat value of 2fold lower than wild type
M190E
the mutant enzyme displays a kcat value of 5.9fold lower than wild type
M190K
R163K
T51S
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the mutant shows increased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
T51S/G52S
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the mutant shows increased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
T51S/K82Q/K99E/N171S
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the mutant shows increased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
T53S/Y258F
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the mutant shows sensitivity towards 5-fluorodeoxyuridine similar to the wild type enzyme
V3A
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the mutant enzyme has an intracellular half-life of approximately 6 h after treatment with cycloheximide
V3F
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the mutant enzyme has an intracellular half-life of approximately 3.5 h after treatment with cycloheximide
V3L
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the mutant enzyme has an intracellular half-life of approximately 2.5 h after treatment with cycloheximide
V3T
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the mutant enzyme has an intracellular half-life of approximately 24 h after treatment with cycloheximide
V3Y
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the mutant enzyme has an intracellular half-life of approximately 2.5 h after treatment with cycloheximide
Y258F
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the mutant shows decreased sensitivity towards 5-fluorodeoxyuridine compared to the wild type enzyme
T155C/E188C/C244T
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formation of 2 disulfide crosslinks across the subunit interface results in dramatic stabilization of the overall structure of the protein, retention of secondary structure at temperatures as high as 90°C, engineering of an intersubunit crosslink yields a fully active enzyme
P2A
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the mutant enzyme is quite stable relative to wild type enzyme with half-life of more than 36-48 h
P2D
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the mutant enzyme is quite stable relative to wild type enzyme with half-life of more than 36-48 h
P2G
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the mutant is unstable relative to wild type enzyme having half-life of 6-8 h similar to wild type
P2R
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the mutant enzyme is quite stable relative to wild type enzyme with half-life of more than 36-48 h
P2V
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the mutant is unstable relative to wild type enzyme having half-life of 1-2 h with half-life of more than 36-48 h
P2W
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the mutant enzyme is quite stable relative to wild type enzyme with half-life of more than 36-48 h
P2Y
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the mutant enzyme is quite stable relative to wild type enzyme with half-life of more than 36-48 h
S290G
site-directed mutagenesis, the mutant shows 10fold reduced activity compared to the wild-type enzyme
additional information
430fold decrease in kcat value, about 30fold increase in Km value for (R)-5,10-methylene-5,6,7,8-tetrahydrofolate. Decrease in binding affinity for folate-like inhibitors
the mutant enzyme displays a kcat value of 6fold lower than wild type
A191K
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the mutant exhibits about 25% of the catalytic activity of the wild type enzyme. The mutant exhibits nonhyperbolic behavior with respect to dUMP and inhibition of catalysis is reversed by substrate saturation
A191K
inactive. Mutant has large areas of hydrophobic region exposed to solvent and exposes the hydrophobic beta-sheets in the dimer interface
the mutant has the value of kcat/Km smaller by a factor of about 7500 than the wild type, the crystal structure of this mutant is similar to that of the wild type with loop 181-197 in the inactive conformation, however, the direct vicinity of the mutation, residues 188-194 of this loop, assumes a different conformation with the positions of Calpha shifted up to 7.2 A, the mutant protein is trapped in an inactive state that does not equilibrate easily with the active conformer
M190K
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the mutant exhibits less than1% of the catalytic activity of the wild type enzyme
M190K
inactive. Mutant has large areas of hydrophobic region exposed to solvent and exposes the hydrophobic beta-sheets in the dimer interface
mutation results in destabilization of inactive conformation. Activity is about 33% higher than in wild-type. Crystallization data show that all subunits of the mutant are in the active conformation, while wild-type crystallizes as the inactive conformer. Structure reveals differences in the environment of catalytic residue Cys195
R163K
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the mutant exhibits an increase in catalytic activity and shows significantly reduced phosphorylation compared to the wild type enzyme
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construction of a cell line expressing the Ugi protein inhibitor of UNG family of uracil DNA glycosylases, which reduces cellular uracil DNA glycosylase activity by at least 45-fold. Genomic uracil levels are increased over 4fold following thymidylate synthase inhibition in the Ugi-expressing cells, but do not detectably increase in UNG proficient cells. No difference in toxicity between the UNG proficient and UNG-inhibited cells to folate or nucleotide-based inhibitors of thymidylate synthase. UNG proficient and UNG-inhibited cells arrest in early S-phase and resume replication progression during recovery from raltitrexed treatment almost identically
additional information
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targeting of mRNA with antisense oligodeoxynucleotides, complementary to the translation start site, the coding region, and the 3' untranslated region. In response to treatment with translation start site-targeting antisense oligodeoxynucleotide 791, thymidylate synthase gene transcription in HeLa cells is increased by 70%. Increased thymidylate synthase gene transcription and nuclear thymidylate synthase RNA do not elevate levels of total cellular thymidylate synthase mRNA, but do increase thymidylate synthase protein activity by 35% and thymidylate synthase protein level by 150%. Increased thymidylate synthase protein activity and level do not alter proliferation rate or sensitivity to thymidylate synthase-targeting drugs
additional information
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mutations of the thyA gene are responsible for the phenotype of trimethoprim-sulfamethoxazole-resistant thymidine-dependent small-colony variants of Staphylococcus aureus
additional information
DHFR activity in lysates of Escherichia coli expressing Tsf-TbDHFR-TS is about 6fold more active than those expressing His6-TbDHFR-TS. In addition, thymidylate synthase activity, which has proved elusive with the His6-protein, is detectable. Stabilization of the TS activity with dUMP, without affect on DHFR stability. No stabilisation observed with CH2THF and other pyrimidine nucleotides, including the uracil-containing ribonucleotides and deoxyribonucleotides, and the thymidine-containing deoxyribonucleotides, overview
additional information
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DHFR activity in lysates of Escherichia coli expressing Tsf-TbDHFR-TS is about 6fold more active than those expressing His6-TbDHFR-TS. In addition, thymidylate synthase activity, which has proved elusive with the His6-protein, is detectable. Stabilization of the TS activity with dUMP, without affect on DHFR stability. No stabilisation observed with CH2THF and other pyrimidine nucleotides, including the uracil-containing ribonucleotides and deoxyribonucleotides, and the thymidine-containing deoxyribonucleotides, overview
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