Structural basis for phosphorylation of adenosine congeners.

Abstract

DURING the past few years the metabolism by mammalian cells of a number of natural and synthetic nucleosides structurally related to adenosine has been investigated in this1–5 and other laboratories6–10. In our studies with Ehrlich ascites cells, we have tried to establish a correlation between the structural variations and the utilization by cells of these nucleosides and have observed the following salient features: (a) In order to be phosphorylated to the 5′-triphosphate level, the adenosine analogue must have a primary amino group at the C-6 position of the purine moiety. Compounds that belong in this category are 3′-deoxyadenosine2,6, 3′-amino-3′-deoxyadenosine4 and 2-fluoroadenosine3. These three nucleosides were also found to be potent inhibitors of nucleic acid synthesis in Ehrlich ascites cells. Work in other laboratories has shown that 7-deazaadenosine7, xylosyladenine8, arabinosyladenine9 and the bases 2-azaadenine and 2,6-diaminopurine10 were also phosphorylated to 5′-triphosphate. 2,6-Diaminopurine is also metabolized to the triphosphate level by microbial cells11,12. Removal of the 6-amino group as in 3′-deoxynebularine resulted in complete absence of phosphorylation by ascites cells*4. (b) 6-Methylaminopurine ribonucleoside—an adenosine analogue with a 6-methyl-amino group—was metabolized to the monophosphate level only4. This was also found to be so for 6-methyl-aminopurine - 2′-deoxyribonucleoside, 6-methylaminopurine-3′-deoxyribonucleoside and 6-methylaminopurine5. (c) Replacement of the 6-amino group by 3′-deoxyadenosine with an ethylamino or dimethylamino group completely suppressed the capacity of the nucleoside for phosphorylation. This relationship was exemplified by 6-ethylaminopurine-3′-deoxyribonucleoside and 6-dimethylaminopurine-3′-deoxyribonucleoside4. Furthermore, 6-dimethylamino-3′-amino-3′-deoxyribonucleoside was also inactive, while its parent compound, as already mentioned, was readily phosphorylated. Nucleosides that were not phosphorylated had almost no effect on nucleic acid synthesis.