Prebiotic cytosine synthesis: A critical analysis and implications for the origin of life
Robert Shapiro*
Author Affiliations
Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003
Communicated by Leslie Orgel, The Salk Institute for Biological Studies, San Diego, CA (received for review November 19, 1998)
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Abstract
A number of theories propose that RNA, or an RNA-like substance, played a role in the origin of life. Usually, such hypotheses presume that the Watson–Crick bases were readily available on prebiotic Earth, for spontaneous incorporation into a replicator. Cytosine, however, has not been reported in analyses of meteorites nor is it among the products of electric spark discharge experiments. The reported prebiotic syntheses of cytosine involve the reaction of cyanoacetylene (or its hydrolysis product, cyanoacetaldehyde), with cyanate, cyanogen, or urea. These substances undergo side reactions with common nucleophiles that appear to proceed more rapidly than cytosine formation. To favor cytosine formation, reactant concentrations are required that are implausible in a natural setting. Furthermore, cytosine is consumed by deamination (the half-life for deamination at 25°C is ≈340 yr) and other reactions. No reactions have been described thus far that would produce cytosine, even in a specialized local setting, at a rate sufficient to compensate for its decomposition. On the basis of this evidence, it appears quite unlikely that cytosine played a role in the origin of life. Theories that involve replicators that function without the Watson–Crick pairs, or no replicator at all, remain as viable alternatives.
Among the most commonly encountered ideas concerning the origin of life is the one that it involved an “RNA world” at an early stage (1). The term was coined by Gilbert (2), who also stated “The first stage of evolution proceeeds, then, by RNA molecules performing the catalytic activities necessary to assemble themselves out of a nucleotide soup.” The existence of such a soup has generally been taken for granted. For example, Eigen and Schuster (3) wrote “The building blocks of polynucleotides—the four bases, ribose and phosphate were available too under prebiotic conditions. Material was available from steadily refilling pools for the formation of polymers, among them polypeptides and polynucleotides.” The experimental evidence to date, however, does not appear to support such claims.
Many problems have arisen with both the prebiotic synthesis and the stability of ribose (4–9). To avoid the need for ribose, some authors have preferred to invoke an RNA-like polymer, with a simpler or more accessible backbone, at the start of life (6,10–16). A pre-RNA world would have come first, during which some substance of this type carried out the genetic functions later taken over by RNA. In the great majority of these theories, Watson–Crick pairing of A with U and of G with C is retained as the basis of genetic template recognition.
These suggestions still presume that the bases adenine, cytosine, guanine, and uracil were readily available on early Earth. I have argued that this presumption is not supported by the existing knowledge of the basic chemistry of these substances (4, 17). If the availability of the Watson–Crick pairs at the start of life appears implausible, then more attention must be given to theories that employ a very different replicator or no replicator at all.
To provide a firm basis for this conclusion, I have undertaken a series of reviews in which I consider in detail the chemical evidence for the availability of the Watson–Crick bases at the start of life. In a previous paper, however, I concluded that current information concerning the availability and chemical properties of adenine did not support the idea that it was used in a replicator at the start of life (17). In this publication, I wish to consider the prebiotic syntheses and the stability of cytosine.
RESULTS AND DISCUSSION
Absence of Cytosine in Meteorites and Electrical Spark Discharge Experiments.
The isolation of adenine and guanine from meteorites has been cited as evidence that these substances might have been available as “raw material” on prebiotic Earth (18). However, acid hydrolyses have been needed to release these materials, and the amounts isolated have been low (17–19). Traces of uracil have also been reported in such analyses (20), but no cytosine at all.
The formation of a substance in an electric spark discharge conducted in a simulated early atmosphere has also been regarded as a positive indication of its prebiotic availability (21). Again, low yields of adenine and guanine have been reported in such reactions, but no cytosine (22). The failure to isolate even traces of cytosine in these procedures signals the presence of some problem with its synthesis and/or stability.
Proposed Prebiotic Cytosine Syntheses.
As bonds from carbon to a hetero atom are more readily constructed than carbon–carbon bonds, cytosine syntheses have usually combined a three-carbon fragment with another bearing a urea-like carbon. The most prominent C-3 fragments used have been cyanoacetylene and its hydrolysis product, cyanoacetaldehyde. These processes are discussed separately below.
Syntheses based on cyanoacetylene.
As shown in Fig. 1(Fig.1), Ferris et al. (23) reported that 0.2 M cyanoacetylene (I) and 2 M cyanate (II) reacted together readily at 30°C to givetrans-cyanovinylurea (III) and unidentified products. Conversion of trans-cyanovinylurea to cytosine (with the cis isomer as a likely intermediate) took place readily at pH 11 or greater. In a more direct preparation, cyanate and cyanoacetylene were heated together at 100°C for 24 hr. In a typical run at low concentration, 0.025 M cyanoacetylene and 0.05 M cyanate (the stoichiometry requires two cyanates per cyanoacetylene) afforded 6% cytosine. The maximum yield observed over all circumstances was 19%.
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