Doudna-Nat-2002-418-222 - insight review articles The...

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insight review articles 222 NATURE | VOL 418 | 11 JULY 2002 | www.nature.com/nature H ow life began on Earth is one of the great scientific mysteries. Molecular biologists have long suspected that RNA molecules were key to the process, in part because RNA has essential roles in a most fundamental process — protein synthesis — within all cells. The first example of an RNA molecule that forms a catalytic active site for a series of precise biochemical reactions was reported 20 years ago: the self-splicing pre-ribosomal RNA (rRNA) of the ciliate Tetrahymena . Although there was only one example, the word ‘ribozyme’ was coined for the general concept of an RNA molecule with enzyme-like activity 1 . The following year catalytic activity was discovered in the RNA component of a ribonucleoprotein enzyme, ribonuclease (RNase) P, providing the first example of a multiple- turnover enzyme using RNA-based catalysis 2 . These findings lent increased credibility to the hypothesis of an RNA world, where RNA served both as the genetic material and the principal cellular enzyme, probably assisted in the latter role by metal ions, amino acids and other small- molecule cofactors. The RNA world hypothesis posits that as cellular metabolism became more sophisticated, increasing demands on biocatalysts provided the impetus for the transition to protein enzymes. Descendants from this proposed RNA-dominated era inhabit today’s world in the form of naturally occurring ribozymes present in organisms ranging from bacteria to humans (Table 1). Although the known natural cellular and viral ribozymes catalyse only phosphodiester transfer chemistry, ribozymes obtained through in vitro selection techniques can exhibit the sort of biochemical sophistication necessary to support cellular metabolism. Starting with a pool of random RNA sequences, molecules possessing a desired activity are isolat- ed through successive cycles of activity selection, reverse transcription of the ‘winners’ into DNA and amplification of those sequences by the polymerase chain reaction. This methodology has allowed identification of ribozymes that form a nucleotide from a base plus a sugar 3 , synthesize amide bonds 4,5 , form Michael adducts such as those involved in the methylation of uridine monophosphate to give thymidine monophosphate 6 , and form acyl-coenzyme A, which is found in many protein enzymes 7 . It is tantalizing to think that these ribozymes are analogues of missing links in a tran- sition from an RNA world to contemporary biology (ref. 8, and see review in this issue by Joyce, pages 214–221). Because the structures and chemical mechanisms of in vitro -selected ribozymes are largely unknown at present, we focus here on the more extensively studied natural ribozymes.
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Doudna-Nat-2002-418-222 - insight review articles The...

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