Pyrimidines prebiotic synthesis

This reaction looks simple, but an enzyme-free prebiotic synthesis, in particular involving pyrimidine bases, is still very difficult. It is possible that completely new synthetic strategies will need to be devised. 

Moderately simple syntheses have been performed for the purines cytosine and uracil but nothing seems to work as a prebiotic synthesis of the pyrimidines. Then adding the sugar ribose to the base makes them nucleosides and one phosphoric acid residue makes it a nucleotide, or specifically a mononucleotide a rare but curiously important sequence of events in present-day life but perhaps not for prebiotic chemistry and early life forms. 

The prebiotic synthesis of pyrimidines is based on cyanoacetylene, which is obtained in good yields by sparking mixtures of methane and nitrogen and by the... 

Figure 3.5 The prebiotic synthesis of pyrimidines of nucleic acids. (From Miller, 1998.)...

Hydrogen cyanide and methanal are especially reasonable starting materials for the prebiotic synthesis of amino acids, purine and pyrimidine bases, ribose and other sugars. Formation of glycine, for example, could have occurred by a Strecker synthesis (Section 25-6), whereby ammonia adds to methanal in the... 

The prebiotic synthesis of the pyrimidine cytosine involves cyanoac-etylene, which is synthesized in good yield by sparking mixtures of CH4 + N2. Cyanoacetylene reacts with cyanate to give cytosine,29... 

The above review shows the progress that has been made in the last 30 years. The prebiotic synthesis of amino acids, purines, pyrimidines, and sugars is understood at a basic level, although more details of the reactions are needed. The polymerization processes are less well understood, and while some of them are plausible it is necessary to work them out in greater detail. The template polymerization reactions are an exciting beginning and may show how genetic information started to accumulate. So far the problem of nucleic acid directed enzyme synthesis has not been dealt with on an experimental level. The problems in this area, which are very difficult, are considered by other speakers in this symposium. 

In spite of the large amount of pyrimidines found in the Murchison meteorite (one fifth of that of purines), only a few instances of prebiotic synthesis of these derivatives have been reported, with the exception of the catalyzed procedures that will be described in the next paragraph. In general, these pro-... 

Prebiotic Synthesis of Purine and Pyrimidine Nudeobases Under Catalytic Conditions... 

Miller reported a plausible prebiotic synthesis of the PNA monomers, which are ethylendiamine (ED), AEG and purine and pyrimidine acetic acid derivatives [222]. Spark discharge experiments with a mixture of CH4, NH3, N2 and H20, using both high and room temperature apparatuses, afforded a low amount of ED and AEG. A better result was obtained for the synthesis of ED by NH4CN polymerization in the presence of H2CO. Scheme 27 shows the mechanism hypothesized for the production of ED from ammonium cynide and HCN trimer. 

An aqueous solution containing ammonia, hydrogen cyanide, and simple organic compounds such as formaldehyde and cyanoethine, in contact with rocks, constituted substrates and the environment for the prebiotic synthesis of more complex organic molecules purine and pyrimidine bases, amino acids, and sugars -the building blocks of all the organisms. 

Ferris JP, Sanchez R, Orgel LE. Studies in prebiotic synthesis III. Synthesis of pyrimidines from cyanoacetylene and cyanate. J Mol Biol 1968 33 693-704. 

Sanchez RA, Orgel LE. Studies in prebiotic synthesis. V. Synthesis and photoanomerization of pyrimidine nucleosides. J. Mol. 91. Biol. 1970 47 531-543. 

The prebiotic synthesis of adenine was confirmed by C. U. Lowe, M. W. Rees and R. Markham, and indirectly by Ponnamperuma and co-workers. The former authors also found the fourth common biological purine, hypoxanthine, in the reaction product from HCN and ammonia mixtures. It may be noted that the above sequence of reactions follows the same direction (first imidazole, then pyrimidine eyclization) as the biochemical synthesis of purines. The kinetics and mechanisms of HCN oligomerization as well as the potential role of the HCN trimer and tetramer for purine synthesis were studied by several investigators, particularly by J. P. Ferris and L. Orgel and coworkers. The yields of purines from HCN are quite low but after isolating the appropriate intermediates, e.g. aminomalonodinitrile (AMN), diaminomaleodinitrile (DAMDN), AICN, AICAI, AICA, and condensing them with formamidine or other one-carbon compounds, substantial yields of adenine and the other purines can be obtained. 

Since pentoses and phosphates were not included in the HCN-NH4OH mixtures one could not expect the formation of nucleosides or nucleoside phosphates in such mixtures, as in the biochemical de novo synthesis of purine nucleotides, even though an adenine derivative of possible nucleosidic nature was detected in one of our early experiments. Alternate biochemical routes also exist (salvage pathways) for the synthesis of nucleosides from the preformed bases. The latter general approach has been followed in the prebiotic synthesis of purine nucleosides, and the former has been used in the synthesis of pyrimidine nucleosides and nucleotides. 

Figure 10. Two possible mechanisms for the prebiotic synthesis of pyrimidines from the reaction of cyanoacetaldehyde with urea concentrated by laboratory models of drying lagoon...

More exotic alternatives to nucleosides have been proposed based on the peptide nucleic acid (PNA) analogues of Nielsen and coworkers (93). Miller and coworkers (94) were able to demonstrate the facile prebiotic synthesis of all of the components of PNA under the same chemical conditions required for the synthesis of the purines or pyrimidines. Nevertheless there are maity alternative structures, which have not yet been investigated. 

Until the 1980s, yields of nucleobases obtained in prebiotic syntheses were very small. Thus, some scientists assumed that in earlier phases of molecular evolution, the nucleic acids used other bases in their information-transmitting substances. Piccirilli et al. (1990) suggested isocytosine and diaminopyridine, while Wachtershauser (1988) suggested that the first genetic material possibly consisted only of purines. However, pyrimidine (about a fifth of the total amount of purines present) had been detected in the Murchison meteorite, so that an effective pyrimidine synthesis should have been possible. 

The synthesis of pyrimidines under specific prebiotic conditions, at low temperature, has apparently been carried out successfully (Fig. 4.8). The formation of the DNA building blocks was carried out by freezing out a dilute solution of cyanoacetaldehyde (CAA) and urea or guanidine. The concentration of CAA was only 1(T3 M, that of guanidine 1M. The reaction took 2 months at 273 K and a pH of 8.1. Yields were as follows ... 

A further unusual feature of the matrix-dependent polycondensation lies in the character of the nucleobases themselves. Purine mononucleotides undergo polycondensation, in good yields, at complementary matrices consisting of pyrimidine polymers. However, the synthesis of pyrimidine oligonucleotides from their mononucleotides at purine matrices is not effective. This important fact means that a pyrimidine-rich matrix leads to a purine-rich nucleic acid, which is itself not suitable to act as a matrix. This phenomenon also occurs when matrices are used which contain both basic species, i.e., purines and pyrimidines. An increase in the amount of purine in a matrix leads to a clear decrease in its effectiveness (Inoue and Orgel, 1983). However, the authors note self-critically that the condensation agent used cannot be considered to be prebiotic in nature. 

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