β_LG values in mechanistic studies on the transesterification of RNA models and their application in a metal ion complex promoted transesterification

Abstract

Studies on the mechanism of transesterification reactions of nucleoside 3′-phosphoesters using b LG values as a mechanistic tool are discussed in this mini review. Our recent observation that a dinuclear metal ion complex enhances both the cleavage and isomerisation is discussed in the light of previous studies. /journal/poc a Calculated from second-order rate constants determined NaOH solutions. b From second-order rate constants obtained from a non-linear fit of log k vs [H + ]. c From second-order rate constants determined in bicarbonate buffers.

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

“…For displacement of basic alkyl groups like 5′O of ribose, catalysis by metal ions and metal ion complexes can result in a decrease in β LG reflecting a decrease in charge accumulation on the leaving group in the TS. 9,22 Possible catalytic interactions involving divalent ions consistent with the available data include electrostatic stabilization of an anionic TS, inner sphere coordination of the nucleophile and leaving groups, and Brønsted acid/base catalysis involving coordinated water molecules 3–5 (Fig. 1B).…”

“…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.…”

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

“…Effects of organometallic complex catalysts on β LG values have been expertly covered by Mikkola and colleagues [37], and current reviews focusing on functional and design properties of organometallic catalysts are also available [38]. Here, we focus on examples where experimental and computational approaches are converging.…”

“…Recently reported QM calculations obtained assuming coordination of both non-bridging oxygens and the nucleophile by the two Zn 2+ atoms in Zn 2 ( 1 )[40] support a concerted mechanism with a later TS, although one that is more associative relative to the uncatalyzed TS, is consistent with the observed KIEs. In contrast, the distinct dinuclear Zn organometallic complex catalyst, Zn 2 ( 2 ) (Figure 3A) is proposed to act by stabilization of a phosphorane intermediate as evidenced by its ability to catalyze both cleavage and isomerization [37]. A β LG of −0.92 is observed for uridine-3′-alkylphosphate reactions catalyzed by Zn 2 ( 2 )[41], compared to −1.28 for specific base catalysis (see above) indicating less charge development on the leaving group [41].…”

“…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]. …”