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

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• 作者：Thomas C. Bruice ; Akira Tsubouchi ; Robert O. Dempcy ; and Leif P. Olson
• 刊名：Journal of the American Chemical Society
• 出版年：1996
• 出版时间：October 16, 1996
• 年：1996
• 卷：118
• 期：41
• 页码：9867 - 9875
• 全文大小：360K
• 年卷期：v.118,no.41(October 16, 1996)
• ISSN：1520-5126

文摘

Adenosine3'-O(PO₂^-)OCH₂R phosphateesters have been synthesized with R =8-hydroxyquinol-2-yl(1a) and 8-(hydroxyquinolyl)-2-methylene (1b).The adenosine3'-O(PO₂^-)OCH₂R structurehas the essential featuresof an RNA dinucleotide. Equilibrium binding studies with metalions Mg²⁺, Zn²⁺, Cu²⁺, andLa³⁺ have been carriedout with 1a, 1b, HOCH₂R (7a and7b), and 8-hydroxyquinoline (8), and equilibriumconstants (K_as) have beendetermined for the formation of 1:1(L)Mⁿ⁺ complexes. Thehydrolysis of 1a and 1b as well as(1a)Mⁿ⁺ and(1b)Mⁿ⁺ species are first order inHO^-. The rate enhancement for hydrolysis of 1aby complexation with metal ions isas follows: ~10⁵ with Zn²⁺,~10³ with Mg²⁺, ~10⁵ withCu²⁺, and ~10⁹ with La³⁺.Molecular modeling indicatesthat metal ions ligated to the 8-hydroxyquinoline moiety in thecomplexes (1a)Mⁿ⁺and (1b)Mⁿ⁺catalyze 1a and 1bhydrolysis by interacting as Lewis acid catalysts with the negativelycharged oxygen atom of the phosphate group.In the instance of La³⁺ complexes, the ligated metalion is within an interactive distance with both thenegativephosphate oxygen and the leaving oxygen. This bimodal assistanceby La³⁺ to the displacement reaction atphosphorusby the 2'-hydroxyl anion results in remarkable rate accelerations forthe hydrolysis of (1a)La³⁺ and(1b)La³⁺ complexes.The complexes(1a)Mⁿ⁺ and(1b)Mⁿ⁺ arethemselves hydrolyzed by metal ion catalysis in a reaction that isfirstorder in HO^-, an observation consistent with a transitionstate composition of[(1a,b)Mⁿ⁺][Mⁿ⁺][HO^-].We assumethe kinetic equivalent[(1a,b)Mⁿ⁺][Mⁿ⁺OH]to represent the reacting species. In this catalysis theMⁿ⁺OH isproposedto play the role of general base to deprotonate the 2'-OH while themetal in the complexes(1a,b)Mⁿ⁺ iscoordinatedto a negative oxygen of the -(PO₂^-)-moiety. This double metal ion catalysis mimics a mechanismproposed forthe ribozyme self-cleavage of RNA.