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Protein Engineering vol. 3 no. 8 pp. 691-701, 1990
© 1990 Oxford University Press

RESEARCH-ARTICLE

Energetics of RNA cleavage: implications for the mechanism of action of ribozymes

Kazunari Taira1, Masami Uebayasi, Hidekatsu Maeda and Kensuke Furukawa2

Fermentation Research Institute, Agency of Industrial Science and Technology MITI, Tsukuba Science City 305, Japan 2Department of Agricultural Chemistry, Faculty of Agriculture, Kyushu University Fukuoka 812, Japan

1To whom correspondence should be addressed

A new class of ribozymes produce 2', 3'-cyclk phosphate upon self-catalyzed cleavage of RNA molecules, similar to those observed during enzymatic (RNase-catalyzed) as well as non-enzymatic hydrolyses of RNAs. This product suggests that the reaction intermediate/transition state is a pentacoordinated oxyphosphorane. In order to elucidate the energetics of these RNA cleaving reactions, the reaction coordinate has been simulated and a pentacoordinated intermediate has been characterized via ab initio molecular orbital calculations utilizing the dianionk hydrolysis-intermediate of methyl ethylene phosphate as a model compound. The calculated reaction coordinate indicates that the transition state for the P–O(2') bond cleavage is lower in energy than that for the P–O(5') bond cleavage under uncatalyzed conditions. Thus, the dianionk pentacoordinated phosphorus intermediate tends to revert back to the starting RNA by cleaving the P–O(2') bond rather than productively cleaving the P–O(5') bond. In order for ribozymes to effectively cleave RNA molecules, it is therefore mandatory to stabilize the leaving 5'-oxygen, e.g. by means of a divalent magnesium ion.

Keywords: ribozymes/2', 3'-cyclic phosphate/RNA cleavage/molecular orbital

Received November 7, 1989; accepted April 26, 1990.


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