Genetic and Biochemical Characteristics of Three Different Types of Mutants of Mammalian Cells Affected in Adenosine Kinase

Abstract

Purine nucleoside analogs constitute an important group of antimetabolites, many of whom possess very useful biochemical and medicinal properties (1, 2). For the past several years we have been investigating the metabolism and mechanism of cellular resistance to a number of different purine nucleoside analogs viz. toyocamycin, tubercidin, 6-methyl mereapto-purineriboside (6-MeMPR), pyrazofurin, formycin A and formycin B in cultured Chinese hamster cells using a combined genetic and biochemical approach (3-7). In this approach cellular mutants resistant to various analogs are initially selected and then their cross resistance patterns towards other nucleoside analogs and the affected cellular functions are examined. Our studies with mutants resistant to the above purine nucleoside analogs in Chinese hamster ovary (CHO) cells show that all of the mutants obtained are affected in the enzyme adenosine kinase (AK), thus providing strong evidence regarding the central role of AK in the cellular metabolism and toxicity of these analogs. Studies with these mutants which are reviewed here show that at least three different types of mutants, which show novel differences in the biochemical properties of the enzyme and in their cross resistance patterns towards N- and C-purine nucleoside analogs have been isolated. (C-Nucleosides are those in which the purine base is linked to ribose via a C-C bond rather than the usual N-C linkage found in adenosine and most other nucleosides (1, 2)).