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Prebiotic Chemistry and the Origin of the RNA World

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Prebiotic Chemistry and the Origin of the RNA World Critical Reviews in Biochemistry and Molecular Biology, 39:99–123, 2004 Copyright c Taylor & Francis Inc. ISSN: 1040-9238 print / 1549-7798 online DOI: 10.1080/10409230490460765 Prebiotic Chemistry and the Origin of the RNA World Leslie E. Orgel The Salk Institute, La Jolla, California, USA a “chicken and egg problem” and to ask which came first, The demonstration that ribosomal peptide synthesis is a proteins or nucleic acids? At the time, it was well recog- ribozyme-catalyzed reaction makes it almost certain that there was nized that natural selection through replication and muta- once an RNA World. The central problem for origin-of-life studies, tion was the only mechanism for evolving complex bio- therefore, is to understand how a protein-free RNA World became chemical systems from simpler ones. Trying to solve the established on the primitive Earth. We first review the literature on “chicken and egg” problem, therefore, was equivalent to the prebiotic synthesis of the nucleotides, the nonenzymatic synthe- asking whether proteins or nucleic acids were more plausi- sis and copying of polynucleotides, and the selection of ribozyme ble as the components of a self-contained replicating sys- catalysts of a kind that might have facilitated polynucleotide repli- tem. The answer seemed obvious: nucleic acids. Watson- cation. This leads to a brief outline of the Molecular Biologists’ Crick base-pairing provided a very plausible mechanism Dream, an optimistic scenario for the origin of the RNA World. In by which a polynucleotide could direct the synthesis of the second part of the review we point out the many unresolved problems presented by the Molecular Biologists’ Dream. This in its complement from mononucleotides or short oligonu- turn leads to a discussion of genetic systems simpler than RNA that cleotides, while no equivalent mechanism was known for might have “invented” RNA. Finally, we review studies of prebiotic the replication of a polypeptide. These arguments were de- membrane formation. veloped in some detail in three overlapping papers (Woese, 1967; Crick, 1968; Orgel, 1968), and a program to explore nonenzymatic copying of nucleic acid sequences was ini- Keywords nucleotide synthesis, polynucleotide formation, RNA tiated (Sulston et al., 1968a, 1968b). For personal use only. replication, prebiotic membranes The authors of the three early papers clearly recognized that an autonomous RNA “organism” would be possi- ble only if RNA could take on several of the functions presently performed by proteins, for example, the func- INTRODUCTION tions of RNA polymerases and nucleases. They speculated that coenzymes incorporating nucleotides in their structure The ideas behind the hypothesis of an RNA World origi- were fossils from a time when RNA functioned without nated in the late 1960s in response to a profound puzzle. the help of proteins (Woese, 1967; Orgel, 1968; Orgel & The basic principles of molecular biology were well un- Sulston, 1971), an idea that was subsequently developed derstood, and it was clear that the replication of nucleic in some detail (White, 1976). In one instance it was spec- acids was dependent on protein enzymes and the synthe- ulated that the original ribosome was composed entirely sis of protein enzymes was dependent on nucleic acids. of RNA (Crick, 1968). However, in none of the papers Even if one allowed for every possible simplification of was it suggested that RNA catalysis was still important in the system, for example, by postulating a nucleic acid with contemporary biology. It was taken for granted that pro- Critical Reviews in Biochemistry and Molecular Biology Downloaded from informahealthcare.com by 67.176.26.7 on 04/08/12 only two bases and proteins assembled from a very limited tein enzymes could always outperform RNA catalysts and suite of amino acids, what remained was too complicated had, therefore, completely replaced them in contemporary to have arisen de novo from an assembly of abiotic organic organisms. molecules. The only way out was to regard the dilemma as The unanticipated discovery of catalytic RNA mole- cules, ribozymes, that perform enzyme-like reactions Editor: Michael M. Cox. (Kruger et al., 1982; Guerrier-Takada et al., 1983) marked Address correspondence to Leslie E. Orgel, The Salk Institute, the beginning of the present interest in a proteinless biolog- 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: orgel@ ical world. In the few years following Cech and Altman’s salk.edu discoveries, ribozymes were shown to be able to catalyze 99 100 L. E. ORGEL a significant number of diverse chemical reactions. This 4. The emergence through natural selection of a set of led to an increased interest in the hypothesis that an RNA functional RNA catalysts that together could sustain World, a term introduced by Gilbert (Gilbert, 1986), pre- exponential growth in the prebiotic environment. ceded the DNA/RNA/Protein world (Gesteland et al., The first three topics are part of the traditional field of 1999). The determination of the structure of the ribosome, prebiotic chemistry, while the fourth is the subject matter showing that it is a ribozyme (Steitz & Moore, 2003), of the newer field of RNA evolution. We begin this review seems to clinch the case for an RNA World, although it by covering the first three topics in some detail. Since the leaves open almost all questions about the origin and “bio- fourth topic falls outside the scope of traditional prebiotic chemistry” of the RNA World. The RNA World hypothesis chemistry, only a very brief overview will be given. From does not deny that peptides may have been involved in the our discussion of prebiotic chemistry we will conclude origin of life. It does, however, exclude the possibility that that the abiotic synthesis of RNA is so difficult that it is any peptides that were involved were formed by ribosomal unclear that the RNA World could have evolved de novo protein synthesis or a closely related mechanism. on the primitive Earth, a conclusion that was first em- The knowledge that an RNA World preceded our famil- phasized by Cairns-Smith (Cairns-Smith & Davies, 1977; iar biochemical world has profound implications for those Cairns-Smith, 1982). Consequently, we will have to con- interested in the origin of life. It may be claimed, without sider different routes to the RNA World. We will explore too much exaggeration, that the problem of the origin of the possibility that a simpler replicating molecule could life is the problem of the origin of the RNA World, and have formed on the primitive Earth and that organisms that everything that followed is in the domain of natural with a genetic system based on that simpler polymer could selection. If this is accepted, studies of the chemistry of the have “invented” RNA. origin of life are, in principle, greatly simplified because they need only be concerned with the origin of RNA and do not need to deal with the origins of most other features PREBIOTIC SYNTHESIS OF NUCLEOTIDES of biochemistry. Of course, the origin of protein synthe- sis and of DNA are also of the greatest interest, but their Prebiotic Synthesis appearance can be regarded as the consequences of selec- Prebiotic chemistry is concerned with molecules that are tion acting on populations of autonomous RNA organisms. interesting to students of the origin of life which, they The focus of this review, therefore, will be the origin of believe, could have been formed on the primitive Earth. the RNA World and its evolution prior to the development Since we know very little about the availability of start- of protein synthesis. We will have little to say about the ing materials on the primitive Earth or about the physical For personal use only. prebiotic synthesis of amino acids, peptides, cofactors, etc. conditions at the site where life began, it is often difficult While acceptance of an RNA World greatly simplifies to decide whether or not a synthesis is plausibly prebi- the problem of the origin of life, it also has a negative aspect otic. Not surprisingly, claims of the type, “My synthesis (Orgel, 2003). If the origin of the RNA World preceded the is more prebiotic than yours” are common. Nonetheless, origin of protein synthesis, little can be learned about the there is fairly general agreement about the following re- chemistry of the origin of life from the study of protein en- strictions on organic synthesis imposed by the requirement zyme mechanisms. The justification of prebiotic syntheses for prebioticity: by appealing to their similarity to enzymatic mechanisms It must be plausible, at least to the proposers of a prebiotic has been routine in the literature of prebiotic chemistry. synthesis, that the starting materials for a synthesis Acceptance of the RNA World hypothesis invalidates this could have been present in adequate amounts at the type of argument. If the RNA World originated de novo site of synthesis. on the primitive Earth, it erects an almost opaque barrier Reactions must occur in water or in the absence of a between biochemistry and prebiotic chemistry. solvent. It is possible that the RNA World was the first organized Critical Reviews in Biochemistry and Molecular Biology Downloaded from informahealthcare.com by 67.176.26.7 on 04/08/12 The yield of the product must be “significant,” at least in biochemical world on the primitive Earth. If we suppose the view of the proposers of the synthesis. that this is the case, the problem of the origin of life can conveniently be divided into a number of subproblems: Clearly “prebiotic” is a very elastic term, and it would not be wise to try to define it too closely. Just as many people have been speaking prose all their 1. The nonenzymatic synthesis of nucleotides.
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