2010
DOI: 10.1021/ja103550e
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Kinetic Isotope Effects for RNA Cleavage by 2′-O- Transphosphorylation: Nucleophilic Activation by Specific Base

Abstract: To better understand the interactions between catalysts and transition states during RNA strand cleavage, primary 18 O kinetic isotope effects and solvent D 2 O isotope effects were measured to probe the mechanism of base-catalyzed 2'-O-transphosphorylation of the RNA dinucleotide 5'-UpG-3'. The observed 18 O KIEs for the nucleophilic 2'-O and in the 5'-O leaving group at pH 14 are both large relative to reactions of phosphodiesters with good leaving groups, indicating that the reaction catalyzed by hydroxide … Show more

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Cited by 47 publications
(129 citation statements)
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“…2 Table 1 for acid-and basecatalyzed 2′-O-transphosphorylation reactions of UpG, together with previous biophysical and biochemical studies, provide a framework for understanding the RNase A transition state. For solution 2′-O-transphosphorylation, previous experimental and computational data are consistent with the observed 18 k NUC being a combination of normal contributions from deprotonation and an inverse effect from advanced 2′O-P bond formation (6,17). Together, these contributions result in the inverse values observed for the stepwise acid-catalyzed reaction (pH 0) and a similar inverse 18 k NUC for the late anionic transition state for base catalysis (pH 12) [0.990(4) and 0.996(2), respectively, with standard deviations in parentheses] (6,(18)(19)(20).…”
Section: Resultssupporting
confidence: 81%
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“…2 Table 1 for acid-and basecatalyzed 2′-O-transphosphorylation reactions of UpG, together with previous biophysical and biochemical studies, provide a framework for understanding the RNase A transition state. For solution 2′-O-transphosphorylation, previous experimental and computational data are consistent with the observed 18 k NUC being a combination of normal contributions from deprotonation and an inverse effect from advanced 2′O-P bond formation (6,17). Together, these contributions result in the inverse values observed for the stepwise acid-catalyzed reaction (pH 0) and a similar inverse 18 k NUC for the late anionic transition state for base catalysis (pH 12) [0.990(4) and 0.996(2), respectively, with standard deviations in parentheses] (6,(18)(19)(20).…”
Section: Resultssupporting
confidence: 81%
“…For solution 2′-O-transphosphorylation, previous experimental and computational data are consistent with the observed 18 k NUC being a combination of normal contributions from deprotonation and an inverse effect from advanced 2′O-P bond formation (6,17). Together, these contributions result in the inverse values observed for the stepwise acid-catalyzed reaction (pH 0) and a similar inverse 18 k NUC for the late anionic transition state for base catalysis (pH 12) [0.990(4) and 0.996(2), respectively, with standard deviations in parentheses] (6,(18)(19)(20). These data are consistent with analyses of nucleophile bonding by LFERs of RNA reactions catalyzed by a specific base, which show that the 2′ oxyanion formed in a preequilibrium deprotonation step undergoes substantial loss of negative charge in the transition state (21).…”
Section: Resultssupporting
confidence: 81%
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