5 Catalytic Strategies of Self-Cleaving Ribozymes: Relics of an RNA World?

Abstract

The evolution of living systems requires efficient and accurate biochemical catalysts. Although most modern enzymes are proteins, the discovery of a few classes of naturally occurring catalytic RNAs, called ribozymes, greatly enhances the credibility of speculation that nucleic acids were the original biocatalysts, in part because RNA plays central roles in the fundamental process of protein biosynthesis in all cells. According to the “RNA World” hypothesis, RNA once both encoded genetic information and possessed the ability to replicate that information faithfully, as well as to catalyze the synthesis of essential chemical building blocks (Joyce 1989). As this primitive RNA-based metabolism evolved, requirements for more sophisticated biocatalysts are thought to have stimulated the transition to protein enzymes. Ribozymes present in viruses and organisms ranging from bacteria to humans may be holdovers from such an RNA-dominated era. If this is true, a subset of catalytic activities performed by modern protein enzymes was originally part of the repertoire of ribozymes. Since the initial discoveries of ribozymes in the early 1980s, much effort has focused on determining how these catalysts achieve exquisite substrate specificity and impressive rate enhancements despite lacking the diversity of functional groups present in proteins. Over the past decade, molecular structures of several ribozymes and their component domains have been determined by X-ray crystallography and solution NMR, revealing how even small RNAs can form complex three-dimensional folds. These structures have in turn guided biochemical experiments intended to dissect ribozyme reaction mechanisms, leading to initial optimism that ribozymes might readily give up...