title: Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates.
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.
authors.affiliation: Department of Industrial Chemistry, Chiba Institute of Technology, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kanou
authors.forename: H
authors.initials: H
authors.lastname: Ohomori
authors.forename: K
authors.initials: K
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Yokoyama
authors.forename: R J
authors.initials: RJ
authors.lastname: Suhadolnik
authors.forename: R
authors.initials: R
authors.lastname: Sobol
authors.forename: H
authors.initials: H
authors.lastname: Takaku
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D002942:Circular Dichroism; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D051379:Mice; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D012335:RNA, Ribosomal; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease