Purines lethal synthesis

With a few notable exceptions—such as puromycin and its relatives, psicofuranine and decoynine, and certain 9-alkylpurines-which will be discussed later, purines and their nucleosides must be anabolized to nucleoside phosphates in order to exert their biological effects. This type of metabolic event has been called a lethal synthesis , because it results in the death of cells that carry it out. 

Purine Antimetabolites. Purine synthesis can be blocked by 6-mercaptopurine (7.77) and 6-thioguanine (7.78). Both require conversion to the mononucleotide in a lethal synthesis —a mechanism distinguished from the formation of suicide substrates in that the enzyme that transforms the inactive pro-dmg to the active inhibitor is different from the enzyme that is being blocked. inhibitors are formed and bound by the same... 

Fig. 4-14). Both 6-mercaptopurine and 6-thioguanine are not active purine inhibitors until they are converted to their respective nucleotides by hypoxanthine-guanine phosphoribo-syl transferase enzymes in the cell. Since this is an intrinsically destructive process to the cell, it is referred to as a lethal synthesis or salvage pathway. Tumor cells or normal cells that have very low levels of this enzyme are resistant to these two agents. Absence of this enzymatic function is not lethal to the cell since the synthesis of purines in the cell can occur by different pathways. 

The damages caused by ionizing radiations in nucleic acid and their components are obviously detrimental to the passage of genetic information that requires specific order of intact purine and pyrimidine bases in the DNA strands. Alterations in these bases and the DNA molecules in general can lead to mutations and lethal genes. The disruption of RNA molecules interferes with protein synthesis and can result in eventual cell death. 

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