The extent of RNA catalysis – are there any limits?
报告题目：The extent of RNA catalysis – are there any limits?
报告人：Professor David M.J. Lilley
时间：2023年8月29号上午10点30分
地点：化学材料综合楼B407-409
主持人：徐亮 教授
报告人简介：
David M.J. Lilley，英国邓迪大学教授，英国皇家科学院院士、英国皇家化学会院士、爱丁堡皇家学会院士，曾任CRC核酸结构研究组主任，在核酸的结构及功能研究方面具有很深的造诣，已在Science，Nature, J. Am. Chem. Soc. Cell, PNAS, Structure 等国际一流期刊发表文章380余篇，并获得很多荣誉，其中包括英国皇家化学学会交叉学科奖，RNA and Ribozyme Chemistry Award of The Royal Society of Chemistry，The Prelog Medal in Stereochemistry Switzerland，The Gold Medal of G. Mendel of the Czech Academy of Sciences 等国际知名奖项。2015年获得RNA学会终身成就奖，2016年荣获皇家化学学会霍拉纳奖（Awarded the Royal Society of Chemistry Khorana Prize）。
报告内容简介：
The RNA world hypothesis for the early development of life on the planet requires that RNA molecules (ribozymes) could have catalysed a wide variety of chemical reactions. Known ribozymes in contemporary biology carry out a limited range of chemical catalysis, mostly involving phosphoryl transfer, and we have a good understanding of many of these. in vitro selection has generated species catalysing a broader range of chemistry. To gauge the feasibility of an RNA world it is useful to explore if ribozymes can exploit sophisticated catalytic strategies.
A ribozyme has recently been selected that can catalyse a methyl transfer reaction using O6-methylguanine as donor. We have solved the crystal structure of this ribozyme at a resolution of 2.3 Å, showing how the RNA folds to generate a very specific binding site for the methyl donor substrate. The structure immediately suggests a catalytic mechanism, involving a combination of proximity and orientation, and nucleobase-mediated general acid catalysis. The mechanism is supported by the pH dependence of the rate of catalysis, and by quantum mechanical calculation. This small chemical machine employs a relatively sophisticated catalytic mechanism, broadening the range of known RNA-catalysed chemistry. This lends new support to the RNA world hypothesis
Going still further, how could RNA overcome its relative chemical simplicity and expand its catalytic repertoire ? The RNA world would have required a much broader range of RNA catalysed chemistry, including “difficult” reactions like making C-C bonds. Modern protein enzymes achieve this by using co-enzymes, and perhaps RNA could do the same. RNA is a superb receptor for small molecules, as exemplified by the riboswitches. A significant number of these bind coenzymes, including SAM, TPP, NAD+ and FMN, and it’s a relatively small step to imagine that the riboswitch might have evolved from an ancient ribozyme, or might be converted into a novel ribozyme.
References:
[1] Lilley. Classification of the nucleolytic ribozymes based upon catalytic mechanism. F1000Research, 8. 1462 (2019)
[2] Deng et al. Structure and mechanism of a methyl transferase ribozyme. Nature Chem Biol 18, 556–564 (2022)
[3] McCarthy et al. Catalytic mechanism and pH-dependence of a methyl transferase ribozyme (MTR1) from computational enzymology. Nucleic Acids Res. 51. 4508-4518 (2023)
[4] Wilson and Lilley. The potential versatility of RNA catalysis. WIREs RNA 12, e1651 (2021).
