Deoxyadenosine triphosphate isolation

Pentostatin (deoxycoformycin Fig. 4) is a purine isolated from cultures of Streptomyces antibioticus. Its mode of action involves inhibition of adenosine deaminase, which plays a key role in purine salvage pathways and DNA synthesis. As a consequence, deoxyadenosine triphosphate (dATP) is accumulated, which is highly toxic to lymphocytes. This is associated with augmented susceptibility to apoptosis, particularly in T cells. 

The consequence of ADA deficiency is accumulation of adenosine and 2 -deoxyadenosine, substances toxic to lymphocytes, important cells in the immune response. 2 -Deoxyadenosine is particularly toxic because its presence leads to accumulation of its nucleotide form, dATP, an essential substrate in DNA synthesis. Elevated levels of dATP actually block DNA replication and cell division by inhibiting synthesis of the other deoxynncleoside 5 -triphosphates (see Chapter 27). Accumulation of dATP also leads to selective depletion of cellular ATP, robbing cells of energy. Children with ADA SCID fail to develop normal immune responses and are susceptible to fatal infections, unless kept in protective isolation. 

Pentostatin also belongs in the antimetabolite category although its mechanism of action is totally different from that of other antimetabolites. Pentostatin is a natural product isolated from the fermentation broth of Streptomyces. It is an example of a dmg which is a transition-state analogue which is believed to mimic the transition state of 2-deoxyadenosine when it is being deamidated (Fig. 21.12). The conversion of 2-deoxyadenosine into 2-deoxyinosine is an important metabolic step in controlling DNA synthesis. If the conversion does not occur, 2-deoxyadenosine accumulates and is converted into its triphosphate (dATP), which is a potent... 

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