One- and Two-Metal Ion Catalysis of the Hydrolysis of Adenosine 3‘-Alkyl Phosphate Esters. Models for One- and Two-Metal Ion Catalysis of RNA Hydrolysis

• Published in: Journal of the American Chemical Society 1996-10, Vol.118 (41), p.9867-9875
• Main Authors: Bruice, Thomas C, Tsubouchi, Akira, Dempcy, Robert O, Olson, Leif P
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9607300

Adenosine 3‘-O(PO2 -)OCH2R phosphate esters have been synthesized with R = 8-hydroxyquinol-2-yl (1a) and 8-(hydroxyquinolyl)-2-methylene (1b). The adenosine 3‘-O(PO2 -)OCH2R structure has the essential features of an RNA dinucleotide. Equilibrium binding studies with metal ions Mg2+, Zn2+, Cu2+, and La3+ have been carried out with 1a, 1b, HOCH2R (7a and 7b), and 8-hydroxyquinoline (8), and equilibrium constants (K as) have been determined for the formation of 1:1 (L)M n + complexes. The hydrolysis of 1a and 1b as well as (1a)M n + and (1b)M n + species are first order in HO-. The rate enhancement for hydrolysis of 1a by complexation with metal ions is as follows:  ∼105 with Zn2+, ∼103 with Mg2+, ∼105 with Cu2+, and ∼109 with La3+. Molecular modeling indicates that metal ions ligated to the 8-hydroxyquinoline moiety in the complexes (1a)M n + and (1b)M n + catalyze 1a and 1b hydrolysis by interacting as Lewis acid catalysts with the negatively charged oxygen atom of the phosphate group. In the instance of La3+ complexes, the ligated metal ion is within an interactive distance with both the negative phosphate oxygen and the leaving oxygen. This bimodal assistance by La3+ to the displacement reaction at phosphorus by the 2‘-hydroxyl anion results in remarkable rate accelerations for the hydrolysis of (1a)La3+ and (1b)La3+ complexes. The complexes (1a)M n + and (1b)M n + are themselves hydrolyzed by metal ion catalysis in a reaction that is first order in HO-, an observation consistent with a transition state composition of [(1a,b)M n +][M n +][HO-]. We assume the kinetic equivalent [(1a,b)M n +][M n +OH] to represent the reacting species. In this catalysis the M n +OH is proposed to play the role of general base to deprotonate the 2‘-OH while the metal in the complexes (1a,b)M n + is coordinated to a negative oxygen of the −(PO2 -)− moiety. This double metal ion catalysis mimics a mechanism proposed for the ribozyme self-cleavage of RNA.