2.7.1.48: uridine/cytidine kinase
This is an abbreviated version!
For detailed information about uridine/cytidine kinase, go to the full flat file.
Word Map on EC 2.7.1.48
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2.7.1.48
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thymidine
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salvage
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uracil
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phosphoribosyltransferase
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phosphorylase
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orotate
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ump
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5-fluorouracil
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5-fluorouridine
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deoxycytidine
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5-azacytidine
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6-azauridine
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3-deazauridine
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orotidine
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pyrazofurin
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medicine
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5-fluoro-2'-deoxyuridine
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3huridine
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dihydrouracil
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drug development
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diagnostics
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biotechnology
- 2.7.1.48
- thymidine
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salvage
- uracil
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phosphoribosyltransferase
- phosphorylase
- orotate
- ump
- 5-fluorouracil
- 5-fluorouridine
- deoxycytidine
- 5-azacytidine
- 6-azauridine
- 3-deazauridine
- orotidine
- pyrazofurin
- medicine
- 5-fluoro-2'-deoxyuridine
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3huridine
- dihydrouracil
- drug development
- diagnostics
- biotechnology
Reaction
Synonyms
ATP:uridine 5'-phosphotransferase, hsUCK2, kinase, uridine (phosphorylating), More, pyrimidine ribonucleoside kinase, ttCK, UCK, UCK1, UCK2, UCKL1, Udk, UK/UPRT1, uridine cytidine kinase 2, uridine kinase, uridine phosphokinase, uridine-cytidine kinase, uridine-cytidine kinase 2, uridine/cytidine kinase, uridine/cytidine kinase 2
ECTree
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General Information
General Information on EC 2.7.1.48 - uridine/cytidine kinase
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drug target
malfunction
metabolism
physiological function
additional information
1-(3-C-ethynyl-beta-D-ribopentofuranosyl)cytosine (ECyd) is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors. ECyd is phosphorylated to 3'-ethynylcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethyntlcytidine 5'-diphosphate, 3'-ethyntlcytidine 5'-triphosphate). 3'-Ethyntlcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively. IVS5 + 5 G > A mutation would affect the expression level of the UCK2 transcript and result in decreased sensitivity to ECyd. The UCK2 is a key drug-response predictive marker for innate or acquired resistance to uridine/cytidine-type nucleoside analogs
drug target
inhibition of enzyme (UCK2) induces nucleolar stress, probably by depleting nucleotide biosynthesis, thereby destabilising ribosomal biogenesis and subsequently causing cancer cell arrest and apoptotic cell death induction
mutagenesis of Tyr93 in ttCK reveals that the uridine phosphorylation activity is restored only by replacement of Tyr93 with His or Gln
malfunction
mutation H117Y of UCK2 results in a loss of uridine phosphorylation activity of the enzyme
malfunction
overexpression of uridine-cytidine kinase 2 correlates with breast cancer progression and poor prognosis. UCK2, along with other genes involved in the 5-FU anabolic pathway, produces a phenotype of cell sensitivity to 5-FU folxadlowing knockdown
malfunction
probable ribosomal stress condition during inhibition of the UCK2 enzyme, overview. The released and subsequent activation of p53 leads towards apoptosis induction
malfunction
role of a uridine/cytidine kinase 2 mutation in cellular sensitiveness toward 3'-ethynylcytidine (ECyd) treatment of human cancer cells. The splice-site mutation of the UCK2 gene resulting in the IVS5+5 G>A variant affects the expression level of the UCK2 transcript, causing decreased sensitivity to ECyd. The IVS5+5 G>A variant generates an aberrant mRNA transcript, namely, truncated mRNA is produced and normal mRNA levels are markedly decreased in the ECyd-resistant cancer cell line HT1080. Relationship of UCK2 mutations and drug sensitivity with ECyd in several cancer cell lines, overview. Detection of the aberrant mRNA transcript in the ECyd/EUrd-resistant cancer cells with the IVS5 +5 A/A genotype
malfunction
UCK from Thermus thermophilus HB8 loses catalytic activity on uridine due to lack of a substrate binding ability and possesses an unusual amino acid, i.e. tyrosine 93 (Tyr93) at the binding site, whereas histidine (His) is located in the other UCKs. Mutagenesis experiments reveal that a replacement of Tyr93 by His or glutamine (Gln) recovers catalytic activity on uridine
malfunction
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mutagenesis of Tyr93 in ttCK reveals that the uridine phosphorylation activity is restored only by replacement of Tyr93 with His or Gln
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malfunction
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UCK from Thermus thermophilus HB8 loses catalytic activity on uridine due to lack of a substrate binding ability and possesses an unusual amino acid, i.e. tyrosine 93 (Tyr93) at the binding site, whereas histidine (His) is located in the other UCKs. Mutagenesis experiments reveal that a replacement of Tyr93 by His or glutamine (Gln) recovers catalytic activity on uridine
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malfunction
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mutagenesis of Tyr93 in ttCK reveals that the uridine phosphorylation activity is restored only by replacement of Tyr93 with His or Gln
-
malfunction
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UCK from Thermus thermophilus HB8 loses catalytic activity on uridine due to lack of a substrate binding ability and possesses an unusual amino acid, i.e. tyrosine 93 (Tyr93) at the binding site, whereas histidine (His) is located in the other UCKs. Mutagenesis experiments reveal that a replacement of Tyr93 by His or glutamine (Gln) recovers catalytic activity on uridine
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uridine-cytidine kinase is the rate-limiting enzyme in the pyrimidine-nucleotide salvage pathway, overview
metabolism
UCK2 is feedback inhibited by UTP and CTP to adjust cellular needs and prevent overproduction of the nucleotides. In the course of cancer cell proliferation, these nucleotides are continuously synthesized to sustain protein synthesis. During gene degradation, some NMPs are released and recycled via the salvage pathway by the action of UCK2, thereby facilitating the prevention of energy loss and the waste of valuable precursors. Molecular crosstalks between UCK2 and cell death, the role of ribosomal proteins, MDM2 and p53 in regulation of cell death, and the role of UCK2 in regulation of cell death
metabolism
the enzyme is responsible for the phosphorylation of uridine and cytidine to their corresponding monophosphate in a salvage pathway of pyrimidine nucleotides biosynthesis
metabolism
Thermus thermophilus HB8 / ATCC 27634 / DSM 579
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uridine-cytidine kinase is the rate-limiting enzyme in the pyrimidine-nucleotide salvage pathway, overview
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a nucleosidic medicine, 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) cytosine [3'-ethynylcytidine (ECyd)], is a potent inhibitor of RNA polymerase I and shows anticancer activity to various human solid tumors in vitro and in vivo. ECyd is phosphorylated to 3'-ethynylcytidine 5'-monophosphate by uridine/cytidine kinase 2 (UCK2) and subsequently further to diphosphate and triphosphate (3'-ethynylcytidine 5'-diphosphate, 3'-ethynylcytidine 5'-triphosphate). 3'-ethynylcytidine 5'-triphosphate is an active metabolite that can inhibit RNA polymerase I competitively, causing cancer cell death
physiological function
enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression, but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlates with UCK2 expression
physiological function
in contrast to other UCK enzymes, UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine
physiological function
the pyrimidine salvage enzyme uridine-cytidine kinase 2 (UCK2) is necessary for uridine salvage. Biological significance of UCK2 in the uridine salvage is measured by incorporating exogenous 5-ethynyl-uridine (5-EU) specifically into cellular RNA
physiological function
UCK2 is responsible for the phosphorylation of uridine and cytidine to their corresponding monophosphate in a salvage pathway of pyrimidine nucleotides biosynthesis. Uridine-cytidine kinase 2 (UCK2) is linked to cell apoptosis induction. Molecular crosstalk involving UCK2 protein and cancer cell death through cell cycle arrest and triggering of apoptosis involving proteins, MDM2 and the subsequent activation of p53. UCK2 is also involved in the phosphorylation of ribonucleoside analogues, 5-azacytidine, cyclopentenyl cytosine/uracil, 5-fluorocytidine, 6-azauridine, 3-deazauridine, 5-fluorouridine as well as ethynyl cytidine and uridine. These cytotoxic drugs depends on the action of the UCK2 enzyme to sequentially transformed into nucleoside 5'-triphosphate, thereby interfering with gene synthesis vital for metabolic processes required for cancer cell growth and maintenance
physiological function
uridine-cytidine kinase (UCK) 2 is a rate-limiting enzyme involved in the salvage pathway of pyrimidine-nucleotide biosynxadthesis. Isozyme UCK2 is overexpressed in many types of cancer and may play a crucial role in activating antitumor prodrugs in human cancer cells. The isozyme catalyzes the phosphorylation of urixaddine and cytidine to form uridine monophosphate (UMP) and cytidine monophosphate (CMP) with efficiency 15 to 20fold higher than that of ubiquitously expressed isozyme UCK1
physiological function
uridine-cytidine kinase (UCK) is one of the enzymes in the nucleoside salvage pathway. UCK generally converts both cytidine and uridine to nucleoside monophosphate using ATP as the phosphate donor
physiological function
uridine-cytidine kinase (UCK) is one of the enzymes in the nucleoside salvage pathway. UCK generally converts both cytidine and uridine to nucleoside monophosphate using ATP as the phosphate donor, but the UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine. This cytidine-restricted activity is thought to depend on residue Tyr93
physiological function
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uridine-cytidine kinase (UCK) is one of the enzymes in the nucleoside salvage pathway. UCK generally converts both cytidine and uridine to nucleoside monophosphate using ATP as the phosphate donor, but the UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine. This cytidine-restricted activity is thought to depend on residue Tyr93
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physiological function
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in contrast to other UCK enzymes, UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine
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physiological function
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uridine-cytidine kinase (UCK) is one of the enzymes in the nucleoside salvage pathway. UCK generally converts both cytidine and uridine to nucleoside monophosphate using ATP as the phosphate donor, but the UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine. This cytidine-restricted activity is thought to depend on residue Tyr93
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physiological function
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in contrast to other UCK enzymes, UCK of Thermus thermophilus HB8 (ttCK) phosphorylates only cytidine
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mechanism underlying nucleoside specificity, overview
additional information
mechanism underlying nucleoside specificity, overview
additional information
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mechanism underlying nucleoside specificity, overview. The histidine residue located near the functional group at position 4 of cytidine or uridine in most UCKs is substituted with tyrosine, Tyr93, in ttCK, due to the naturally occuring polymorphism Y93, the UCK homologue ttCK of Thermus thermophilus HB8 has, unlike other UCKs, a substrate specificity towards only cytidine and shows no inhibition by UTP, uridine does not bind to ttCK as substrate. Replacement of Tyr93 by histidine or glutamine endows ttCK with phosphorylation activity toward uridine
additional information
mechanism underlying nucleoside specificity, overview. The histidine residue located near the functional group at position 4 of cytidine or uridine in most UCKs is substituted with tyrosine, Tyr93, in ttCK, due to the naturally occuring polymorphism Y93, the UCK homologue ttCK of Thermus thermophilus HB8 has, unlike other UCKs, a substrate specificity towards only cytidine and shows no inhibition by UTP, uridine does not bind to ttCK as substrate. Replacement of Tyr93 by histidine or glutamine endows ttCK with phosphorylation activity toward uridine
additional information
molecular dynamics simulations on the wild-type Thermus thermophilus enzyme, two mutant ttCKs, and a human UCK bound to cytidine and three protonation forms of uridine to elucidate their substrate specificity, overview. Three residues, Tyr88, Tyr/His/Gln93 and Arg152 in ttCKs, are important for recognizing the substrates. Arg152 contributes to induce a closed form of the binding site to retain the substrate, and the N3 atom of uridine needs to be deprotonated. Although Tyr88 tightly binds cytidine, it does not sufficiently bind uridine because of lack of the hydrogen bonding. His/Gln93 complements the interaction of Tyr88 and raises the affinity of ttCK to uridine. The crucial distinction between Tyr and His or Gln is a role in the hydrogen-bonding network. Therefore, the ability to form both hydrogen-bonding donor and acceptor is required to bind both uridine and cytidine. Residue interactions and kinetics. Tyr59 and Phe90 form Pi-Pi stackings and CH-Pi interaction with cytidine, and Ile113 interacts with cytidine via a hydrophobic interaction. Tyr88, His93, and Arg152 form hydrogen bonds with the cytidine base moiety, and Asp60 and Arg142 anchor the ribose moiety, role of His/Gln93 in complementing the interaction between Tyr88 and the substrate
additional information
uridine phosphorylation activity commonly depends on a single residue in the UCK family. Molecular docking analysis. Structure comparison of Thermus thermophilus enzyme ttCK and human enzyme hsUCK2
additional information
uridine phosphorylation activity commonly depends on a single residue in the UCK family. Structure comparison of Thermus thermophilus enzyme ttCK and human enzyme hsUCK2
additional information
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uridine phosphorylation activity commonly depends on a single residue in the UCK family. Structure comparison of Thermus thermophilus enzyme ttCK and human enzyme hsUCK2
additional information
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uridine phosphorylation activity commonly depends on a single residue in the UCK family. Molecular docking analysis. Structure comparison of Thermus thermophilus enzyme ttCK and human enzyme hsUCK2
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additional information
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molecular dynamics simulations on the wild-type Thermus thermophilus enzyme, two mutant ttCKs, and a human UCK bound to cytidine and three protonation forms of uridine to elucidate their substrate specificity, overview. Three residues, Tyr88, Tyr/His/Gln93 and Arg152 in ttCKs, are important for recognizing the substrates. Arg152 contributes to induce a closed form of the binding site to retain the substrate, and the N3 atom of uridine needs to be deprotonated. Although Tyr88 tightly binds cytidine, it does not sufficiently bind uridine because of lack of the hydrogen bonding. His/Gln93 complements the interaction of Tyr88 and raises the affinity of ttCK to uridine. The crucial distinction between Tyr and His or Gln is a role in the hydrogen-bonding network. Therefore, the ability to form both hydrogen-bonding donor and acceptor is required to bind both uridine and cytidine. Residue interactions and kinetics. Tyr59 and Phe90 form Pi-Pi stackings and CH-Pi interaction with cytidine, and Ile113 interacts with cytidine via a hydrophobic interaction. Tyr88, His93, and Arg152 form hydrogen bonds with the cytidine base moiety, and Asp60 and Arg142 anchor the ribose moiety, role of His/Gln93 in complementing the interaction between Tyr88 and the substrate
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additional information
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uridine phosphorylation activity commonly depends on a single residue in the UCK family. Molecular docking analysis. Structure comparison of Thermus thermophilus enzyme ttCK and human enzyme hsUCK2
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additional information
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molecular dynamics simulations on the wild-type Thermus thermophilus enzyme, two mutant ttCKs, and a human UCK bound to cytidine and three protonation forms of uridine to elucidate their substrate specificity, overview. Three residues, Tyr88, Tyr/His/Gln93 and Arg152 in ttCKs, are important for recognizing the substrates. Arg152 contributes to induce a closed form of the binding site to retain the substrate, and the N3 atom of uridine needs to be deprotonated. Although Tyr88 tightly binds cytidine, it does not sufficiently bind uridine because of lack of the hydrogen bonding. His/Gln93 complements the interaction of Tyr88 and raises the affinity of ttCK to uridine. The crucial distinction between Tyr and His or Gln is a role in the hydrogen-bonding network. Therefore, the ability to form both hydrogen-bonding donor and acceptor is required to bind both uridine and cytidine. Residue interactions and kinetics. Tyr59 and Phe90 form Pi-Pi stackings and CH-Pi interaction with cytidine, and Ile113 interacts with cytidine via a hydrophobic interaction. Tyr88, His93, and Arg152 form hydrogen bonds with the cytidine base moiety, and Asp60 and Arg142 anchor the ribose moiety, role of His/Gln93 in complementing the interaction between Tyr88 and the substrate
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additional information
Thermus thermophilus HB8 / ATCC 27634 / DSM 579
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mechanism underlying nucleoside specificity, overview
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additional information
Thermus thermophilus HB8 / ATCC 27634 / DSM 579
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mechanism underlying nucleoside specificity, overview. The histidine residue located near the functional group at position 4 of cytidine or uridine in most UCKs is substituted with tyrosine, Tyr93, in ttCK, due to the naturally occuring polymorphism Y93, the UCK homologue ttCK of Thermus thermophilus HB8 has, unlike other UCKs, a substrate specificity towards only cytidine and shows no inhibition by UTP, uridine does not bind to ttCK as substrate. Replacement of Tyr93 by histidine or glutamine endows ttCK with phosphorylation activity toward uridine
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