Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle.
Analogs of the 2',5'-linked adenylate trimer diphosphate (pp5'A2'p5'A2'p5'A or 2-5A) containing 8-bromoadenosine in the first, second, third, first and third, or second and third nucleotide positions (from the 5' terminus) were synthesized and found to vary dramatically in their ability to bind to and activate the RNase L of mouse L cells. Whenever the 8-bromoadenosine residue was substituted for adenosine in the first or 5'-terminal residue, there resulted a marked decrease in ability to bind to the 2-5A-dependent endonuclease. A similar result was obtained when the second adenosine nucleotide was replaced by 8-bromoadenosine. To the contrary, all analogs that bore an 8-bromoadenosine (br8A) in the third or 2'-terminal position were bound about as well as parent 2-5A to RNase L. Additionally, the 5'-diphosphate pp5'A2'p5'A2'p5' (br8A) was 10 times more effective than 2-5A as an inhibitor of translation. An increase in stability could not explain this significantly enhanced ability since the 2'-terminally brominated analog showed a similar half-life to 2-5A itself. Finally of particular interest was the analog monophosphate p5'A2'p5'(br8A)2'p5'(br8A) which possessed nearly 10% of the translational inhibitory activity of 2-5A triphosphate itself. These results suggest that changes in the base-sugar torsion angles of 2-5A may modulate both binding to and activation of mouse L cell RNase L.[1]References
- Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle. Lesiak, K., Torrence, P.F. J. Biol. Chem. (1987) [Pubmed]
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