Activation of deoxycytidine kinase by deoxyadenosine

Implications in deoxyadenosine-mediated cytotoxicity

Gergely Keszler, Szula Virga, T. Spasokoukotskaja, P. Bauer, M. Sasvári, M. Staub

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency.

Original languageEnglish
Pages (from-to)69-77
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume436
Issue number1
DOIs
Publication statusPublished - Apr 1 2005

Fingerprint

Deoxycytidine Kinase
Cytotoxicity
Chemical activation
Deamination
Adenosine Deaminase
deoxyadenosine kinase
Deoxyadenine Nucleotides
Adenosine Deaminase Inhibitors
Pentostatin
Pyrimidine Nucleotides
Lymphocytes
Cladribine
Salvaging
Deoxycytidine
Phosphorylation
2'-deoxyadenosine
Nucleosides
Digestion
Intercellular Signaling Peptides and Proteins
Phosphotransferases

Keywords

  • 2-Chlorodeoxyadenosine
  • Adenosine deaminase
  • Cytotoxicity
  • Deoxycytidine kinase
  • Limited trypsinolysis
  • MAP kinase signalling
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

@article{5b8205558f594a9c859776b006993542,
title = "Activation of deoxycytidine kinase by deoxyadenosine: Implications in deoxyadenosine-mediated cytotoxicity",
abstract = "The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency.",
keywords = "2-Chlorodeoxyadenosine, Adenosine deaminase, Cytotoxicity, Deoxycytidine kinase, Limited trypsinolysis, MAP kinase signalling, Tyrosine kinase inhibitors",
author = "Gergely Keszler and Szula Virga and T. Spasokoukotskaja and P. Bauer and M. Sasv{\'a}ri and M. Staub",
year = "2005",
month = "4",
day = "1",
doi = "10.1016/j.abb.2005.01.009",
language = "English",
volume = "436",
pages = "69--77",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Activation of deoxycytidine kinase by deoxyadenosine

T2 - Implications in deoxyadenosine-mediated cytotoxicity

AU - Keszler, Gergely

AU - Virga, Szula

AU - Spasokoukotskaja, T.

AU - Bauer, P.

AU - Sasvári, M.

AU - Staub, M.

PY - 2005/4/1

Y1 - 2005/4/1

N2 - The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency.

AB - The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency.

KW - 2-Chlorodeoxyadenosine

KW - Adenosine deaminase

KW - Cytotoxicity

KW - Deoxycytidine kinase

KW - Limited trypsinolysis

KW - MAP kinase signalling

KW - Tyrosine kinase inhibitors

UR - http://www.scopus.com/inward/record.url?scp=14744284064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14744284064&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2005.01.009

DO - 10.1016/j.abb.2005.01.009

M3 - Article

VL - 436

SP - 69

EP - 77

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 1

ER -