Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates

Biochem Biophys Res Commun. 1991 Apr 30;176(2):769-74. doi: 10.1016/s0006-291x(05)80251-7.

Abstract

Analogues of the 2',5'-linked adenylate trimers monophosphate (p5'A2'p5'A2'p5'A) containing 8-hydroxypropyladenosine, 8-bromoadenosine, and 8-hydroxyadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. p5'AHPr2'p5'AHPr2'p5'AHPr (pAHPr3) (1b) and p5'ABr2'p5'ABr2'p5'ABr (pABr3) (1d) were markedly decreased in ability to bind to the 2-5A dependent endonuclease. On the other hand, analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide position was bound about as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1e) to RNase L. Additionally, p5'AOH2'p5'AOH2'p5'AOH (pAOH3) (1c) was as active as parent 2-5A in the rRNA cleavage assay, while pAHPr3 (1b) and pABr3 (1d) were devoid of activity. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Finally of particular interest was monophosphate, pAOH3 (1c) which possessed nearly 100% of the translation 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / metabolism*
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Circular Dichroism
  • Endoribonucleases / metabolism*
  • Enzyme Activation
  • Mice
  • Nucleic Acid Conformation
  • Oligoribonucleotides / metabolism*
  • RNA, Ribosomal / metabolism

Substances

  • Adenine Nucleotides
  • Oligoribonucleotides
  • RNA, Ribosomal
  • 2',5'-oligoadenylate
  • Endoribonucleases
  • 2-5A-dependent ribonuclease