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Chemical Etiology of the Structure of Nucleic Acids

A. Eschenmoser, R. Krishnamurthy, T. Wagner, M. Beier, F. Reck, T. Mueller, P. Waldmeier, G. Ceulemans, R. Micura

In its second year, research in our group focused on 3 projects.

PENTOPYRANOSYL-(4´2´)-OLIGONUCLEOTIDE SYSTEMS

Ribo-, lyxo-, xylo-, and arabinopyranosyl-(4´/right arrow/2´)-oligonucleotides, in which the nucleobases at the anomeric center are all in equatorial position, constitute diastereomeric members of a family of constitutional isomers of RNA. According to chemical reasoning, they also could have been candidates for Nature's choice of a genetic system. A systematic comparison, at the chemical level, of the base-pairing properties of these potential nucleic acid alternatives with the corresponding properties of RNA may provide clues as to why RNA, rather than one of these alternatives, became the prevailing genetic system.

During the past year, we synthesized the 2 members of the pentopyranosyl-(4´/right arrow/2´)-oligonucleotide family that had been inaccessible: the xylopyranosyl and the arabinopyranosyl systems. Contrary to our expectations, base pairing is strong in both systems, and, most remarkably, the arabinopyranosyl system has a pairing strength greater than that of any known oligonucleotide system, natural or artificial (Fig. 1). Amazingly, we found complete base-pairing promiscuity among the 4 pentopyranosyl systems; all 4 cross-pair efficiently with each other, but none of them cross-pairs with RNA.

The observations made so far clearly indicate that a genetic system was not selected on the basis of maximal base-pairing strength. The search for the relevance of other selection criteria, such as a system's potential for self-replication, will be pursued.

The availability of a complete set of 4 diastereomeric oligonucleotide systems that differ only in the relative configuration of their substituents at the pyranosyl sugar building block offers a unique opportunity to study the structural factors that determine base-pairing properties in oligonucleotide systems in general and to extend current rationalizations of the pairing properties of natural nucleic acids.

CHEMISTRY OF PYRANOSYL-RNA

Of the alternatives to RNA, pyranosyl-RNA, the nucleic acid that consists of the same building blocks as RNA, is the one studied most extensively. Most recently, we examined the correlation between interstrand base stacking and duplex properties, such as thermal duplex stability, effect of dangling bases on duplex stability, and circular dichroism spectral properties. A comparative study of selected base sequences from both the pyranosyl-RNA and the previously synthesized homo-DNA series revealed a remarkably consistent opposite sequence dependence of these properties in the 2 systems. The rationale for this finding is the opposite direction of the inclination between backbone and base-pair axes--and, therefore, sequence dependence of interstrand stacking--in pyranosyl-RNA and homo-DNA. We expect that backbone inclination will be a useful parameter for the structural classification of oligonucleotide duplexes. A hypothetical chemical property of pyranosyl-RNA related to interstrand base stacking is mediation of peptide synthesis through preorganization of p-RNA--bound /alpha/-amino acid building blocks on a p-RNA template; this problem is being investigated.

REGIOSELECTIVE PHOSPHORYLATION OF CARBOHYDRATES

Regioselective phosphorylation of sugars under potentially natural conditions is a long-standing problem of classical prebiotic chemistry. We showed the existence of a strictly regioselective phosphorylation of the /alpha/-position of aldosugars (glycolaldehyde, glyceraldehyde, threose and erythrose, ribose, arabinose, xylose and lyxose) under mild reaction conditions with amidotriphosphate, a phosphorylating agent derived from metatriphosphate by reaction with ammonia. The regioselectivity of the process is the result of an intramolecular nucleophilic substitution within the reversibly formed substrate-reagent adduct. The process is a new addition to the list of chemical processes that may have prebiotic significance and is expected to open a new pathway for the formation of mononucleotides.

PUBLICATIONS

Eschenmoser, A. Thoughts and experiments on a chemical etiology of nucleic acid structure. In: Pioneering Ideas for the Physical and Chemical Sciences. Fleischhacker, W., Schönfeld, T. (Eds.). Plenum, New York, 1997, p. 41.

Groebke, K., Hunziker, J., Fraser, W., Peng, L., Diederichsen, U., Zimmermann, K., Holzner, A., Leumann, C., Eschenmoser, A. Why pentose- and not hexose-nucleic acids? Part V. Purine-purine pairing in homo-DNA: Guanine, isoguanine, 2,6-diaminopurine, and xanthine. Helv. Chim. Acta 81:375, 1998.