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In all of biology, there is no more consequential problem than the origin of life; yet despite the expenditure of much effort and ink over the past seventy years a satisfactory answer continues to elude us. This chapter surveys the huge body of experimental and theoretical work on this problem. Topics include the primordial broth of abiotic chemicals, prebiotic synthesis of metabolites, the quest for a self-replicating ribozyme, the critical importance of energy coupling, self-organized metabolic cycles, why membranes are essential, and the importance of natural selection from the outset. The recent idea, that life arose in the interstices of mineral deposits at the margins of warm alkaline hydrothermal vents, receives special attention. Between the first proto-cells and the Last Universal Common Ancestor, all the machinery of life must have been invented. We consider the place of the RNA World, and the horrendous difficulty of envisaging the origin of translation. In the end, the origin of life remains a mystery that passes understanding.

The most fundamental distinction in biology is between nucleic acids, with their role as carriers of information, and proteins, which generate the phenotype. In existing organisms, nucleic acids and proteins mutually presume one another. The former, owing to their template activity, store the heritable information: the latter, by enzymatic activity, read and express this information. It seems that neither can function without the other. Which came first, nucleic acids or proteins? There are three possible answers: (1) nucleic acids; (2) proteins; (3) neither: they coevolved. In this chapter, we discuss various possible answers to this ‘chicken or egg?’ problem. In section 5.2, we discuss what seems to us the most likely answer, that at first RNA performed both functions, as replicator and enzyme. In section 5.3, we consider an alternative view, in which protein enzymes existed either before, or alongside, the first nucleic acids. In section 5.4, we ask whether, perhaps, the first replicators were not nucleic acids. Finally, in section 5.5, we ask why, given that the genetic message is carried by nucleic acids, there are only four nucleotides and two base pairs. So far, we have tacitly assumed nucleic acids preceeded proteins, without stating the main reason. Nucleic acids came first because they can perform both functions: they are replicable, and they can have enzymatic activity. For many years, a common opinion was that to be replicable almost amounted to self-replicative ability, but that it was far-fetched to assume enzymatic activity. Today, there is increasing evidence that RNA can act as an enzyme, but we are more aware of the difficulty of self-replication. It should have been expected on theoretical grounds that RNA could act as an enzyme: the possibility was discussed by Woese (1967), Crick (1968) and Orgel (1968). Consider first why proteins can act as enzymes. An enzyme has a well-determined three-dimensional structure of chemical groups that, in most cases, arises automatically from the primary structure. Substrates of the enzyme are bound by the chemical groups on the surface. This means that the reactants will be kept in close proximity, and hence experience a much higher local concentration of each other than in solution. This by itself increases the rate of the reaction.

Phosphotransferases, phosphatases, and nucleotidyltransferases catalyze nucleophilic substitution at phosphorus. They constitute a dominant class of enzymes in intermediary metabolism, energy transduction, nucleic acid biosynthesis and processing, and regulation of many cellular processes, including replication, cellular development, and apoptosis. The mechanisms of the action of these enzymes have been studied intensively at several levels, ranging from the biosynthesis of metabolites and nucleic acids to unmasking signaling networks to elucidating the molecular mechanisms of catalysis. We focus on the chemical mechanisms of the reactions of biological phosphates. More than 40 years of research on this chemistry reveals that the mechanisms can be grouped into two classes: the phosphoryl group (PO3−) transfer mechanisms and the nucleotidyl or alkylphosphoryl group (ROPO2−) transfer mechanisms. Because the fundamental chemical mechanisms of these reactions are not treated in textbooks, we begin by considering this chemistry and then move on to the enzymatic reaction mechanisms. Phosphomonoesters, phosphoanhydrides, and phosphoramidates undergo substitution at phosphorus by transfer of the phosphoryl (PO3–) group, that is, by P—O and P—N cleavage. The current description of a typical phosphoryl group transfer mechanism is one in which the phosphoryl donor and acceptor interact weakly with the phosphoryl group in flight in a transition state in which the total bonding to phosphorus is decreased relative to the ground state. The bonding is weak between phosphorus and the leaving group R–X and between phosphorus and the accepting group Y in the transition state of. Because of decreased bonding to phosphorus, this is a loose transition state that has been described as dissociative. The latter should not be confused with the dissociative mechanism, which is considered later. To avoid confusion, we use the term loose transition state. Detailed studies indicate that the bonding denoted by the dashed lines in represents partial covalency on the order of 10% to 20% of the strength of a full covalent bond, or a bond order of 0.1 to 0.2.

The origin of the code is perhaps the most perplexing problem in evolutionary biology. The existing translational machinery is at the same time so complex, so universal, and so essential that it is hard to see how it could have come into existence, or how life could have existed without it. The discovery of ribozymes has made it easier to imagine an answer to the second of these questions, but the transformation of an ‘RNA world’ into one in which catalysis is performed by proteins, and nucleic acids specialize in the transmission of information, remains a formidable problem. We start, in section 6.1, by discussing changes known to have occurred in the code since its origin. Although these changes are minor, they do shed some light on how the code may have evolved in its very early days. In section 6.2, we ask what can be deduced from the present assignment of codons to amino acids, and from the phytogeny of tRNAs. Finally, in section 6.3, we come to grips with the hardest question: how did a specific association between particular amino acids and particular codons first come into existence? It is this association that is the essence of the code. Today, it plays a role in translation, but we think it first arose to serve quite a different function. If so, this is an example of a common feature of evolution: structures that today serve a complex function arose first to serve a simpler one. For many years the common genetic code was thought to be universal. Recently, some interesting exceptions have been found. These are of two types: either a stop codon is used to code for an amino acid, or a codon has been reassigned to a different amino acid. At first sight it is hard to see how this could happen. To alter the meaning of a codon in one particular gene might be a selective advantage, just as any mutation might be, but to alter its meaning wherever it occurs throughout the genome must surely be disastrous.