title: Catalysis of amide synthesis by RNA phosphodiester and hydroxyl groups.
abstract: The functional groups found among the RNA bases and in the phosphoribose backbone represent a limited repertoire from which to construct a ribozyme active site. This work investigates the possibility that simple RNA phosphodiester and hydroxyl functional groups could catalyze amide bond synthesis. Reaction of amine groups with activated esters would be catalyzed by a group that stabilizes the partial positive charge on the amine nucleophile in the transition state. 2'-Amine substitutions adjacent to 3'-phosphodiester or 3'-hydroxyl groups react efficiently with activated esters to form 2'-amide and peptide products. In contrast, analogs in which the 3'-phosphodiester is replaced by an uncharged phosphotriester or is constrained in a distal conformation react at least 100-fold more slowly. Similarly, a nucleoside in which the 3'-hydroxyl group is constrained trans to the 2'-amine is also unreactive. Catalysis of synthetic reactions by RNA phosphodiester and ribose hydroxyl groups is likely to be even greater in the context of a preorganized and solvent-excluding catalytic center. One such group is the 2'-hydroxyl of the ribosome-bound P-site adenosine substrate, which is close to the amine nucleophile in the peptidyl synthesis reaction. Given ubiquitous 2'-OH groups in RNA, there exists a decisive advantage for RNA over DNA in catalyzing reactions of biological significance.
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill 27599-3290, USA.
authors.forename: Stacy I
authors.initials: SI
authors.lastname: Chamberlin
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Weeks
mesh_terms: D000215:Acylation; D000577:Amides / Q000378:metabolism*; D002384:Catalysis; D006900:Hydroxylation; D007700:Kinetics; D009690:Nucleic Acid Conformation; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D012313:RNA; D010727:Phosphoric Diester Hydrolases