Abstract
There are currently more than 20 nucleoside analogs registered for use as antiviral or anticancer drugs. Nucleoside analogs are pro-drugs that after uptake into cells need activation by phosphorylation to form nucleotides that serve as inhibitors for viral or cellular DNA or RNA synthesis. The initial 5′-phosphorylation, carried out by nucleoside kinases, is usually the rate limiting step in the activation of nucleoside analogs. This chapter reviews the major advancements in the biochemistry and molecular genetics related to the cellular deoxynucleoside kinases. There are four deoxynucleoside kinases in animal cells, the two cytosolic enzymes—deoxycytidine kinase (dCK) and thymidine kinase (TK1), as well as two mitochondrial enzymes—thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK). An overview of the properties, structure, and regulation of these cellular deoxynucleoside kinases is presented in the chapter. The genes for cellular deoxynucleoside kinases are now sequenced and the proteins can be expressed in recombinant form in relatively large amounts. This has enabled the determination of the dGK structure, which, in turn, provided good models for the structures of dCK and TK2 since these enzymes belong to the same enzyme family.
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