There is no universal mechanism for the cleavage of RNA model compounds in the presence of metal ion catalysts

Abstract

The transesterification of uridine 3'-phosphodiesters with a wide range of leaving group alcohols has been studied in the presence of monometallic and bimetallic complexes. The catalysis of isomerization of the phosphodiester bond was studied with a nucleoside 3'-phosphonate as a substrate. The results obtained are consistent with a step-wise mechanism, where metal ions are able to enhance both the nucleophilic attack and the departure of the leaving group. The mechanism of the catalysis depends on the acidity of the catalyst and of the leaving group alcohol: a change from general base catalysis to general acid catalysis is proposed. Catalysis of the isomerization requires efficient stabilization of the phosphorane by strong interactions with the catalyst. Catalytic strategies utilised by bimetallic complexes are also briefly discussed.

Isotope effect analyses provide evidence for an altered transition state for RNA 2′-O-transphosphorylation catalyzed by Zn2+

“…9,10,12,14,21 The pH dependences of the rate constants for RNA cleavage reactions catalyzed by metal ions are typically consistent with base catalysis. Often an apparent p K a consistent with the titration of metal coordinated water molecules is also observed.…”

“…Models for Zn 2+ transition state stabilization have proposed general acid catalysis involving a metal coordinated water or hydronium ion. 21,22 In this mechanism Δp K a of +0.85 in D 2 O for the metal coordinated water would increase the concentration of the active form of the catalyst. This effect in turn would impart an inverse $(k_{{\mathrm{H}}_2\mathrm{normalO}}/k_{{\mathrm{D}}_2\mathrm{normalO}}<1)$ value of φ R of ca.…”

Altered (transition) states: mechanisms of solution and enzyme catalyzed RNA 2′-O-transphosphorylation

“…In contrast to the less negative β LG observed for alkyl phosphates, catalysis by Zn 2+ aquo ions results in a more negative β LG for reactions of aryl leaving groups (−0.9), compared to specific base catalysis (−0.54), indicating greater charge accumulation in the TS compared to less reactive alkyl leaving groups. An emerging general feature appears to be that better (aryl) leaving groups depart as anions that can be stabilized by positive charge (resulting in a more negative β LG ), but departure of less reactive (alkyl) groups like in RNA require greater charge stabilization offered by general acid catalysis (and a correspondingly less negative β LG )[43](Figure 3). …”

“…Potential for different catalytic modes depending on leaving group reactivity. Differences in β LG values for catalysis by Zn 2+ alone and by different dinuclear organometallic catalysts indicate different effects on transphosphorylation reactions with good (aryl) ( B ) versus poor (alkyl) ( C ) leaving groups [37,43]. …”

Comparative structure activity relationship for heterogeneous phosphatase-like catalytic activities of one-dimensional Cu(ii) coordination polymers

“…22 In the proposed catalytic mechanism, formation of cyclic transition state was further supported by 31 P NMR spectroscopy for complex 1. 22 In the proposed catalytic mechanism, formation of cyclic transition state was further supported by 31 P NMR spectroscopy for complex 1.…”