Deoxynucleoside Kinases and Their Potential Role in Deoxynucleoside Cytotoxicity

Abstract

Deoxynucleoside kinases are pivotal for the cytotoxic effect of anticancer and antiviral nucleoside analogs. The transfer of a phosphate group from a nucleotide phosphate donor, mostly adenosine triphosphate, to the 5′-OH group of the nucleoside is the key step in the activation of the analog. In human cells, there are four deoxynucleoside kinases with overlapping specificities that together are responsible for the activation of a broad spectrum of nucleoside analogs. Deoxycytidine kinase has the most relaxed specificity and today is the kinase toward which most of the currently used analogs, such as ara-C (cytarabine, Cytosar); dFdC (Gemzar, gemcitabine); CdA (2-chlorodeoxyadenosine, cladribine); and CAFDA (clofarabine, Clofarex) are directed. However, the cytosolic and S-phase-specific thymidine kinase 1 also plays an important role; it is responsible for the activation of the antiviral drug zidovudine (AZT) and, to a lesser degree, d4T (stavudine). Until recently, the two mitochondrial deoxynucleoside kinases, thymidine kinase 2 (TK2) and dGK (deoxyguanosine kinase), have not been in focus as drug-targeting enzymes, but the accumulating knowledge of the role these kinases play for the integrity of mitochondrial deoxyribonucleic acid and their role in apoptosis have increased interest. The efficient cytotoxic effect of drugs like CdA (cladribine) and ara-G (nelarabine) are likely to be caused by the induction of the apoptotic caspase cascade by the corresponding nucleotides. The deoxynucleoside kinases are thought to be evolutionarily closely related to and originate through duplication of a single gene. Then, only a few changes of residues in the active site were necessary for changing the specificity from pyrimidine to purine nucleosides. A thorough and detailed knowledge of the molecular basis for substrate specificity will be a valuable tool for design and development of new and more efficient nucleoside analogs for cancer chemotherapy and viral diseases.Key WordsDeoxynucleosidesdeoxyribonucleosideskinasesnucleoside analogsdeoxynucleoside kinasessalvageenzyme evolutionchemotherapy.