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Prebiotic synthesis on minerals: bridging the prebiotic and RNA worlds.

An array of experimental findings suggest that the simple molecules required for the origin of life may have been available on the primitive Earth. The well-known Miller-Urey electric discharge experiment yields HCN, amino acids, and carboxylic acids (1). Carbonaceous meteorites contain over 70 amino acids, some heterocyclic compounds, including purines, and carboxylic acids. Other organics may have been synthesized under the reducing conditions present in hydrothermal systems (2). Although some of these organics may have been present on the primitive Earth, there is no agreement on which was the most important for their formation. The Miller-Urey experiment requires the presence of either hydrogen gas or reduced carbon and hydrogen compounds, such as methane, carbon monoxide, and ammonia, in the atmosphere of the primitive Earth. Most geochemists believe that the Earth's crust was not reducing when life originated, so the volcanic emissions that resulted in the primitive atmosphere were also not reducing. The notion that comets, meteorites, and asteroids delivered reduced organics to the surface of the primitive Earth is not favored by those who believe that, when these bodies hit the Earth's atmosphere, the organic compounds present on them would have been pyrolyzed. The hydrothermal synthesis of reduced organics is a relatively new hypothesis that is just now undergoing experimental evaluation.

Assuming that the requisite starting materials were available on the primitive Earth (2), and providing conditions that plausibly occurred at that time, I have undertaken to investigate how monomers, particularly mononucleotides, may have condensed to biopolymers (i.e., polynucleotides). Some studies suggest that mononucleotides could have formed from the simpler molecules present on the primitive Earth. Oro (3) first reported the synthesis of adenine from concentrated solutions of HCN and ammonia. These studies could be extended to more dilute solutions of HCN (0.01 M) with the aid of a photochemical rearrangement of a tetramer of HCN [ILLUSTRATION FOR FIGURE 1 OMITTED](3). The imidazole intermediates formed in the synthesis of adenine were demonstrated to be intermediates in the synthesis of an array of other purines. The pyrimidines uracil and orotic acid are formed directly from HCN, whereas uracil and cytosine are formed from cyano-acetylene [ILLUSTRATION FOR FIGURE 2 OMITTED](3). As noted previously, carbonaceous meteorites were also a potential source of purines.

The reaction of these bases with ribose to form nucleosides has been investigated (1). Purine nucleosides are formed in low yield in the reaction with ribose when the mixture is heated in the dry state in the presence of the divalent ions ([ILLUSTRATION FOR FIGURE 3 OMITTED], equation 1). Pyrimidine nucleosides are not formed under these reaction conditions. The condensation of formaldehyde to ribose is not an efficient reaction, but the condensation of glycolaldehyde phosphate and formaldehyde to the 2,4-diphosphate of ribose does proceed efficiently (4). The phosphorylation of nucleosides to nucleotides proceeds under dry heating conditions ([ILLUSTRATION FOR FIGURE 3 OMITTED], equation 2). Many of these proposed prebiotic reactions do not proceed efficiently, and we must still determine whether other synthetic conditions will lead to more convincing prebiotic routes. Our investigation of the prebiotic synthesis of RNA is based on the assumption that the polymerization of monomers to polymers proceeded on mineral surfaces. This assumption is made because there is no evidence that long biopolymers form spontaneously in aqueous solution in the absence of enzymes (5). Minerals could have served as prototypical enzymes by selectively adsorbing organics from a mixture of other compounds and catalyzing the self-condensation of these monomers to oligomers. In initial studies, dimers and trimers were formed by the carbodiimide-mediated reaction of 5[prime]-mononucleotides on montmorillonite (1). Polynucleotides were obtained by the reaction of an aqueous solution of the 5[prime]-phosphorimidazolides of mononucleotides (ImpN, [ILLUSTRATION FOR FIGURE 4 OMITTED], equation 1) on montmorillonite (6-8; Kawamura and Ferris, unpubl. data). The phosphorimidazolides of adenosine, inosine, cytidine, and uracil yielded oligomers containing 10-15 monomer units, whereas hexamers were the longest oligomers formed from ImpG.

In addition to catalyzing phosphodiester bond formation, montmorillonite also influences the regiochemistry of the phosphodiester link produced. The nucleotides of the purines adenine and hypoxanthine yield mainly 3[prime],5[prime]-linked phosphodiester bonds (67% and 90%, respectively), while the pyrimidine nucleotides of uracil and cytosine yielded predominantly 2[prime],5[prime]-linked nucleotides (50%-75%). The dimers and trimers formed from the reaction of ImpN in the absence of montmorillonite contain about 90% 2[prime],5[prime]-linkages.

The regioselectivity for phosphodiester bond formation also varies with the activating group used. The use of 1-methyladenine or 4-dimethylaminopyridine as activating groups ([ILLUSTRATION FOR FIGURE 4 OMITTED], line 2) results in the formation of oligomers in which 90% of the phosphodiester bonds are 3[prime],5[prime]-linked (9, 10).

One of the tenets of the proposed RNA world is that the sequence information of the RNA formed by prebiotic processes was preserved by template-directed synthesis (11). We tested this tenet by using the heterogeneous oligo(C)s formed by montmorillonite catalysis as templates for the formation of the complementary oligo(G)s. These oligo(C)s contain mainly 2[prime],5[prime]-links along with 3[prime],5[prime] - and pyrophosphates bonds (7); in addition, both straight-chain and cyclic oligomers are present as products. The complementary oligo(G)s were formed when the heterogeneous template was treated with 5[prime]-GMP activated by 2-methylimidazole ([ILLUSTRATION FOR FIGURE 4 OMITTED], line 2). Both 2[prime],5[prime]- and 3[prime],5-linked oligo(G)'s were formed in this template-directed synthesis. Even when all the 3[prime],5[prime]-links were removed from the oligo(C)s, a template that directed the synthesis of the complementary oligo(G)s still resulted. Thus, the information content of the heterogeneous oligomers formed by mineral catalysis or by other prebiotic routes could have been maintained by template-directed synthesis.

The other characteristic of the proposed RNA world would have been its ability to catalyze the reactions of other organics. It is not likely that the 10-15-mers formed by clay mineral catalysis have sufficient 3-dimensional tertiary structure to bind and catalyze the reactions of other RNAs. But oligo(A)s as long as 50 mers could be made in 14 days in so-called "feeding reactions," where an activated monomer (ImpA) was added daily to a decameric primer bound to the montmorillonite [ILLUSTRATION FOR FIGURE 5 OMITTED] (12). Oligomers with a median number of 30 bases and as long as 50 bases were detected as reaction products. These oligomers may be long enough to exhibit catalytic activity (13, 14). This experiment suggests that long oligomers may have been formed on the primitive Earth by activated monomers reacting with short oligomers bound to the surface of a catalytic mineral. What remains to be done is to prepare, on montmorillonite, oligomers containing two or more complementary bases in a feeding reaction, and to test the mixture of polynucleotides that forms for catalytic activity. If catalysis is found in this experiment, we will have demonstrated that RNAs possessing the two essential elements for the RNA world - information storage and catalysis - form from simple monomers.


I thank my skillful collaborators, listed in the references, who supplied many of the ideas and most of the experimental studies outlined in this review. The research was supported by NSF grant CHE-9619149 and, in part, by NASA grant NAG 5-4557.

Literature Cited

1. Ferris, J. P. 1987. Prebiotic synthesis - problems and challenges. Cold Spring Harbor Symposia on Quantitative Biology 52: 29-35.

2. Ferris, J. P. 1992. Marine hydrothermal systems and the origin of life: chemical markers of prebiotic chemistry in hydrothermal systems. Origins Life Evol. Biosphere 22: 109-134.

3. Ferris, J. P., and W. J. Hagan, Jr. 1984. HCN and chemical evolution: the possible role of cyano compounds in prebiotic synthesis. Tetrahedron 40: 1093-1120.

4. Eschenmoser, A. 1994. Chemistry of potentially prebiological natural products. Origins Life Evol. Biosphere 24: 389-423.

5. Ferris, J. P. 1993. Catalysis and prebiotic RNA synthesis. Origins Life Evol. Biosphere 23: 307-315.

6. Ferris, J. P., and G. Ertem. 1993. Montmorillonite catalysis of RNA oligomer formation in aqueous solution. A model for the prebiotic formation of RNA. J. Am. Chem. Soc. 115: 12270-12275.

7. Ertem, G., and J. P. Ferris. 1997. Template-directed synthesis using heterogeneous templates produced by montmorillonite catalysis. A possible bridge between the prebiotic and RNA worlds. J. Am. Chem. Soc. 119: 7197-7201.

8. Ding, P. Z., K. Kawamura, and J. P. Ferris. 1996. Oligomerization of uridine phosphorimidazolides on montmorillonite: a model for the prebiotic synthesis of RNA on minerals. Origins Life Evol. Biosphere 26: 151-171.

9. Prabahar, K. J., T. D. Cole, and J. P. Ferris. 1994. Effect of phosphate activating group on oligonucleotide formation on montmorillonite: the regioselective formation of 3[prime],5[prime]-linked oligoadenylates. J. Am. Chem. Soc. 116: 10914-10920.

10. Prabahar, K. J., and J. P. Ferris. 1997. Adenine derivatives as phosphate-activating groups for the regioselective formation of 3[prime],5[prime]linked oligoadenylates on montmorillonite: possible phosphate-activating groups for the prebiotic synthesis of RNA. J. Am. Chem. Soc. 119: 4330-4337.

11. Gilbert, W. 1986. The RNA world. Nature 319: 618. 12. Ferris, J. P., A. R. Hill, Jr., R. Liu, and L. E. Orgel. 1996. Synthesis of long prebiotic oligomers on mineral surfaces. Nature 381: 59-61.

13. Joyce, G. F., and L. E. Orgel. 1993. Prospects for understanding the origin of the RNA World. Pp. 1-25 in The RNA World, R. F. Gesteland and J. F. Atkins, eds. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.

14. Szostak, J. W., and A.D. Ellington. 1993. In vitro selection of functional RNA sequences. Pp. 511-53 in The RNA World, R. F. Gesteland and J. F. Atkins, eds. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.


FORTERRE: Have you, or do you plan to, do the same kind of experiment that you have described at different temperatures? Specifically, are you planning to look at high temperature? RNA is a very thermolabile molecule, which presents a problem for the hypothesis that life originated at very high temperature. We have shown that DNA is stabilized against thermodegradation by physiological salt concentrations (1), but we don't know how RNA behaves at high temperature in the presence of clay or salt.

FERRIS: We've done the RNA synthesis at high temperature. The reaction is not strongly temperature dependent. I've done some work on the stability of RNAs on clays that can catalyze formation and breakdown. Pyrimidine-containing RNAs tend to break down more readily than those containing purine. I can't say much more than that about stability.

REYSENBACH: Have you looked at lower pH conditions?

FERRIS: At lower pH, with the activated phosphates that we use, a competing reaction occurs. The basic leaving groups become protonated, and the rate of hydrolytic reaction of these activated derivatives becomes greater; this causes a competing hydrolysis of the activating group at lower pHs.

UNIDENTIFIED; Why have you neglected the roles of the natural polyamines in these syntheses?

FERRIS: The polyamines will bind exceedingly strongly to the clay, especially if the clay has somewhat acidic surfaces. We haven't necessarily neglected polyamines, we just haven't gotten around to them. Orgel and co-workers (2, 3, 4) have looked at the 2[prime], 3[prime]-cyclic phosphate of nucleotides in anhydrous conditions in the presence of ethylenediamine and similar polyamines. They find that the cyclic phosphates will polymerize in the absence of water, whereas the reaction does not proceed efficiently in the presence of water.

ELLINGTON: Why are you focusing on monomer addition rather than oligomer ligation?

FERRIS: We find that monomer addition works very well. On the other hand, our preliminary studies on ligation reactions, where we hooked dimers together using carbodiimide, didn't work very well. The latter reaction tended to hook the phosphates together to form pyrophosphate linkages.

Literature Cited

1. Marguet, T., and P. Forterre. 1994. DNA stability at temperatures typical for hyperthermophiles. Nucl. Acid. Res. 22: 1681-1686.

2. Renz, M., R. Lohrmann, and L. E. Orgel. 1971. Catalysts for the polymerization of adenosine cyclic 2[prime],3[prime]-phosphate on a Poly (U) template. Biochim. Biophys. Acta 240: 463-471.

3. Verlander, M. S., R. Lohrmann, and L. E. Orgel. 1973. Catalysts for the self-polymerization of adenosine cyclic 2[prime],3[prime]-phosphate. J. Mol. Evol. 2: 303-306.

4. Verlander, M. S., and L. E. Orgel. 1974. Analysis of high molecular weight material from the polymerization of adenosine cyclic 2[prime],3[prime]phosphate. J. Mol. Evol. 3:115-120.
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Title Annotation:Evolution: A Molecular Point of View
Author:Ferris, James P.
Publication:The Biological Bulletin
Date:Jun 1, 1999
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