The synthesis of potentially natural nucleic acid alternatives and comparison of some of their chemical properties with those of RNA and DNA have led to findings that we consider to be relevant in the context of a chemical etiology of nucleic acid structur

Eschenmoser, A.

Krishnamurthy, R.

RERO DOC Digital Library

Pure Appl. Chem., Vol. 72, No. 3, pp. 343–345, 2000.© 2000 IUPAC343*Lecture presented at the 5th International IUPAC Symposium on Bioorganic Chemistry (ISBOC-5), Pune, India, 30 January–4 February, 2000. Other presentations are published in this issue, pp. 333–383.†Corresponding authorChemical etiology of nucleic acid structure*A. Eschenmoser† and R. KrishnamurthyThe Skaggs Institute for Chemical Biology, TSRI, La Jolla, California 92037, USA;Laboratorium für Organische Chemie, ETH, CH-8092 Zürich, SwitzerlandAbstract: The synthesis of potentially natural nucleic acid alternatives and comparison ofsome of their chemical properties with those of RNA and DNA have led to findings that weconsider to be relevant in the context of a chemical etiology of nucleic acid structure.Chemical etiology of nucleic acid structure refers to systematic experimental studies aimed at narrowingthe diversity of possible answers to the question of why nature chose the structure type of ribofuranosylnucleic acids, rather than some other family of molecular structures, as the molecular basis of life’sgenetic system. The experimental strategy is to conceive potentially natural alternatives to the nucleicacid structure, to synthesize such alternatives by chemical methods, and to compare them with thenatural nucleic acids with respect to those chemical properties that are fundamental to the biologicalfunction of RNA and DNA (Fig. 1).In the course of these studies it was found that all four members of the family of pentopyranosyl-(4'Æ2')-oligonucleotide systems that contain b-ribo, b-xylo-, a-lyxo- or a-arabinopyranosyl units asrepeating sugar building blocks are found to be much stronger Watson–Crick base-pairing systems thanRNA [1–3]. The a-arabinopyranosyl system is the strongest of all, in fact, it belongs to the strongestoligonucleotide base-pairing systems known. We conclude that, whatever the chemical determinants bywhich nature selected RNA as a genetic system, maximization of base-pairing strengths within thedomain of pentose-derived oligonucleotide systems was not the critical selection criterion [4] (Fig. 2).The so far experimentally most comprehensively studied system among the potentially naturalsugar-based nucleic acid alternatives is the pyranosyl isomer of RNA. One of the chemical properties ofthis system provides a transparent illustration of the intrinsic potential of an informational oligomersystem to break molecular mirror symmetry. Hemi-self-complementary p-RNA tetramer-2',3'-cyclophosphates were shown to undergo efficient self-templating ligation to higher oligomers with highsequence-, regio-, and chiro-selectivity. Tetramers with differing, but fitting, hemi-complementary basesequences can undergo stochastic co-oligomerization to give rise to large libraries of p-RNA sequences.The high chiroselectivity of the ligation process leads one to think of a scenario in which a comprehen-sively stochastic co-oligomerization process starting from the heterochiral and strictly racemic libraryof all eight possible diastereomers of all possible tetramer-2',3'-cyclophosphates (256 = 44) would nec-essarily break molecular mirror symmetry of higher oligomers in the sense that the resulting (equalamounts of) homochiral D- and L-libraries of a given (high) oligomer would not constitute a racemicmixture since the two libraries would have to have different sequence compositions by statistical rea-sons (Fig. 3).A thought-experiment in which this kind of capacity of an informational oligomer system iscombined with a capability of such (largely) homochiral libraries to undergo self-selection by molecu-lar evolution points to a way of how, in principle, biomolecular homochirality could have emergedwithout a need for any chiral influence from the physical environment [5].344 A. ESCHENMOSER et al.© 2000 IUPAC, Pure and Applied Chemistry 72, 343–345REFERENCES1. M. Beier, F. Reck, T. Wagner, R. Krishnamurthy, A. Eschenmoser. Science 283, 699 (1999).2. O. Jungmann, H. Wippo, M. Stanek, H. K. Huynh, R. Krishnamurthy, A. Eschenmoser. Org.Letters 1, 1527 (1999).3. F. Reck, H. Wippo, R. Kudick, R. Krishnamurthy, A. Eschenmoser. Org. Letters 1, 1531 (1999).4. A. Eschenmoser. Science 284, 2118 (1999).5. M. Bolli, R. Micura, A. Eschenmoser. Chem. Biol. 4, 309 (1997).Fig. 1 Oligonucleotide systems studied. Boxed formulas represent systems that show base-pairing.Chemical etiology of nucleic acid structure 345© 2000 IUPAC, Pure and Applied Chemistry 72, 343–345Fig. 2 Base-pairing strength landscape of pentose-derived oligonucleotide systems (Tm’s of duplexes A8/T8,10 mM, 1M NaCl).Fig. 3 Breaking of molecular mirror symmetry by stochastic chiroselective co-oligomerization inoligonucleotide systems.

Chemical etiology of nucleic acid structure

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library