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Literature summary for 2.7.1.74 extracted from

  • Amsailale, R.; Van Den Neste, E.; Arts, A.; Starczewska, E.; Bontemps, F.; Smal, C.
    Phosphorylation of deoxycytidine kinase on Ser-74: impact on kinetic properties and nucleoside analog activation in cancer cells (2012), Biochem. Pharmacol., 84, 43-51.
    View publication on PubMed
Search for more literature for 2.7.1.74

Activating Compound

Activating Compound Comment Organism Structure
aphidicolin increases dCK activity via Ser74 phosphorylation, effect of aphidicolin treatment on dCK activity in leukemic cells with substrate deoxycytidine and cladribine and other substrates, overview Homo sapiens

Application

Application Comment Organism
additional information deoxycytidine kinase is a key enzyme in the activation of several therapeutic nucleoside analogues Homo sapiens

Protein Variants

Protein Variants Comment Organism
S74E site-directed mutagenesis, the mutation sensitizes the enzyme to feedback inhibition by dCTP, regardless of the phosphoryl donor. Mimicking Ser74 phosphorylation by a S74E mutation increases the enzyme activity toward pyrimidine analogues. The S74E mutation increased the kcat for cladribine by 8 or 3fold, depending on whether the phosphoryl donor was ATP or UTP, for clofarabine by about 2fold with both ATP and UTP, and for fludarabine by 2fold, but only with UTP Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
dCTP a potent inhibitor of the enzyme when ATP is the phosphoryl donor, but a relatively weak inhibitor when the enzyme activity is measured with UTP as the phosphoryl donor. Inhibition is higher with respect to cladribine than deoxycytidine Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.00007
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.00009
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.00018
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.00027
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
0.00065
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.0016
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.0024
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.0087
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.0155
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
0.0155
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.022
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.028
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.0325
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
0.142
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.45
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.551
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol
-
 Homo sapiens 5829
-

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.
ATP + cladribine Homo sapiens
-
 ADP + cladribine 5'-phosphate
-
 ?
ATP + clofarabine Homo sapiens
-
 ADP + clofarabine 5'-phosphate
-
 ?
ATP + deoxyadenosine Homo sapiens
-
 ADP + dAMP
-
 ?
ATP + deoxycytidine Homo sapiens
-
 ADP + dCMP
-
 ?
ATP + deoxyguanosine Homo sapiens
-
 ADP + dGMP
-
 ?
ATP + fludarabine Homo sapiens
-
 ADP + fludarabine 5'-phosphate
-
 ?
UTP + cladribine Homo sapiens
-
 UDP + cladribine 5'-phosphate
-
 ?
UTP + clofarabine Homo sapiens
-
 UDP + clofarabine 5'-phosphate
-
 ?
UTP + deoxyadenosine Homo sapiens
-
 UDP + dAMP
-
 ?
UTP + deoxycytidine Homo sapiens
-
 UDP + dCMP
-
 ?
UTP + deoxyguanosine Homo sapiens
-
 UDP + dGMP
-
 ?
UTP + fludarabine Homo sapiens
-
 UDP + phospho-fludarabine
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein phosphorylation of deoxycytidine kinase on Ser74 increases the enzyme activity, increasing dCK activity via Ser74 phosphorylation, e.g. by aphidicolin, can enhance the intracellular activation of some nucleoside analogs, like gemcitabine, but not of cladribine or fludarabine, overview Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
chronic lymphocytic leukemia cell
-
 Homo sapiens
-
HCT-116 cell
-
 Homo sapiens
-
HT-29 cell
-
 Homo sapiens
-
leukemia cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + cladribine
-
 Homo sapiens ADP + cladribine 5'-phosphate
-
 ?
ATP + clofarabine
-
 Homo sapiens ADP + clofarabine 5'-phosphate
-
 ?
ATP + deoxyadenosine
-
 Homo sapiens ADP + dAMP
-
 ?
ATP + deoxycytidine
-
 Homo sapiens ADP + dCMP
-
 ?
ATP + deoxyguanosine
-
 Homo sapiens ADP + dGMP
-
 ?
ATP + fludarabine
-
 Homo sapiens ADP + fludarabine 5'-phosphate
-
 ?
additional information deoxycytidine kinase shows broad substrate specificity, catalyzing the phosphorylation of deoxycytidine, deoxyadenosine, and deoxyguanosine with ATP or UTP as phosphoryl donor Homo sapiens ?
-
 ?
UTP + cladribine
-
 Homo sapiens UDP + cladribine 5'-phosphate
-
 ?
UTP + clofarabine
-
 Homo sapiens UDP + clofarabine 5'-phosphate
-
 ?
UTP + deoxyadenosine
-
 Homo sapiens UDP + dAMP
-
 ?
UTP + deoxycytidine
-
 Homo sapiens UDP + dCMP
-
 ?
UTP + deoxyguanosine
-
 Homo sapiens UDP + dGMP
-
 ?
UTP + fludarabine
-
 Homo sapiens UDP + phospho-fludarabine
-
 ?

Synonyms

Synonyms Comment Organism
dCK
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.015
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.021
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.0804
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.123
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.172
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
0.177
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.183
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
0.211
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.363
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
0.486
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
0.88
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
1.005
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
1.11
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
1.334
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
1.386
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
2.45
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.6
-
 assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
 Homo sapiens
UTP
-
 Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.0015
-
 dCTP pH 7.6, 37°C, enzyme mutant S74E, with substrates cladribine and ATP, mixed inhibition Homo sapiens
0.0029
-
 dCTP pH 7.6, 37°C, enzyme mutant S74E, with substrates deoxycytidine and ATP, mixed inhibition Homo sapiens
0.0058
-
 dCTP pH 7.6, 37°C, wild-type enzyme, with substrates cladribine and ATP, mixed inhibition Homo sapiens
0.027
-
 dCTP pH 7.6, 37°C, enzyme mutant S74E, with substrates cladribine and UTP, uncompetitive inhibition Homo sapiens
0.03
-
 dCTP pH 7.6, 37°C, wild-type enzyme, with substrates deoxycytidine and ATP, mixed inhibition Homo sapiens
0.05
-
 dCTP pH 7.6, 37°C, wild-type enzyme, with substrates cladribine and UTP, uncompetitive inhibition Homo sapiens
0.052
-
 dCTP pH 7.6, 37°C, enzyme mutant S74E, with substrates deoxycytidine and UTP, uncompetitive inhibition Homo sapiens
0.398
-
 dCTP pH 7.6, 37°C, wild-type enzyme, with substrates deoxycytidine and UTP, uncompetitive inhibition Homo sapiens

General Information

General Information Comment Organism
additional information deoxycytidine kinase is a key enzyme in the activation of several therapeutic nucleoside analogues Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
1.8
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
2.6
-
 fludarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
3
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
6.4
-
 fludarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
50.1
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
56.3
-
 clofarabine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
57.6
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
74.3
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
76.8
-
 clofarabine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
90.2
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
130
-
 cladribine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
136
-
 cladribine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens
236
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate ATP Homo sapiens
257
-
 deoxycytidine pH 7.6, 37°C, wild-type enzyme, with co-substrate UTP Homo sapiens
676
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate ATP Homo sapiens
745
-
 deoxycytidine pH 7.6, 37°C, enzyme mutant S74E, with co-substrate UTP Homo sapiens