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Literature summary for 3.6.1.12 extracted from
- The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine (2016), Biochem. J., 473, 2635-2643 .
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | the enzyme is a factor involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy | Homo sapiens |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene DCTPP1, quantitative real-time PCR enzyme expression analysis | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | gene DCTPP1 silencing by siRNA | Homo sapiens |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| additional information | - |
additional information | Michaelis-Menten kinetics | Homo sapiens |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Homo sapiens |  |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| dCTP + H2O | Homo sapiens | - |
dCMP + diphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
| Homo sapiens | Q9H773 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| HeLa cell | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| aza-dCTP + H2O | the enzyme can hydrolyse the activated form of decitabine, aza-dCTP, and might constitute a novel route in the detoxification of this DNA-methylation inhibitor | Homo sapiens | dCMP + diphosphate | - |
? | |
| dCTP + H2O | - |
Homo sapiens | dCMP + diphosphate | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| dCTP pyrophosphatase 1 | - |
Homo sapiens |
| DCTPP1 | - |
Homo sapiens |
| pyrophosphohydrolase | - |
Homo sapiens |
Temperature Optimum [°C]
| Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 25 | - |
assay at | Homo sapiens |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | exposure of HeLa cells to decitabine upregulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase | up |
| Homo sapiens | exposure of HeLa or MRC-5 cells to decitabine (5-aza-2'-deoxycytidine, aza-dCyd), an anti-cancer drug, upregulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | down-regulation of the enzyme increases decitabine-induced toxicity in HeLa and MRC-5 cells at a wide range of doses | Homo sapiens |
| malfunction | dUTPase or DCTPP1 downregulation enhances the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Downregulation of DCTPP1 or dUTPase increases the toxic effect of decitabine in HeLa cells or in the non-tumoral cell line MRC-5. In contrast, cells transfected with the non-targeting siRNA pool do not exhibit a decrease in viability even in the presence of 0.1 mM decitabine. The protective effect is specific for decitabine since the absence of DCTPP1 or dUTPase do not have a significant impact on cell proliferation after exposure to the canonical nucleoside deoxycytidine or to the cytidine analogue cytarabine. DCTPP1 or dUTPase-deficient cells incubated with decitabine also display a reduced colony-forming capacity compared with control cells | Homo sapiens |
| metabolism | DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two house-cleaning nucleotidohydrolases involved in the elimination of non-canonical nucleotides. Exposure of HeLa cells to decitabine upregulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. In addition to the formation of aza-dCTP (5-aza-2'-deoxycytidine-5'-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor | Homo sapiens |
| metabolism | the enzyme contributes to the cellular response to the anti-cancer nucleoside decitabine. Exposure of HeLa cells to decitabine upregulates the expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase. DCTPP1 down-regulation enhances the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA | Homo sapiens |
| additional information | decitabine (5-aza-2x02-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. It upregulates the enzyme in HeLa cells. Decitabine is metabolically activated in vivo through consecutive phosphorylations into aza-dCTP (5-aza-2'-deoxycytidine-5'-triphosphate) that is readily incorporated into DNA and extended by the DNA polymerase. Once in DNA, decitabine acts as a suicidal substrate by covalently trapping DNMT (DNA methyltransferase) molecules that attempt to initiate cytosine methylation. The resulting DNA-protein cross-links trigger the proteasomal degradation machinery and lead to the depletion of the DNA methylation activities of the cell. Consequently, the replacement of deoxycytidine by decitabine results in hypomethylation at the promoter DNA regions and the reactivation of epigenetically repressed genes | Homo sapiens |
| physiological function | DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy | Homo sapiens |
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