News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998
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.
Ribopyranosyl-, lyxopyranosyl-, xylopyranosyl-, and arabinopyranosyl-(4´→2´)-oligonucleotides,
in which the nucleobases at the anomeric center are all in the equatorial position,
constitute diastereomeric members of a family of constitutional isomers of RNA.
According to chemical reasoning, they also could have been possible 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, eventually became Nature's genetic system.
During the past year, we synthesized the 2 members that had remained inaccessible,
namely, the xylopyranosyl- and the arabinopyranosyl-(4´→2´)-oligonucleotide
systems. The base-pairing properties of both were surprising. In contrast to
expectation, strong base pairing occurs in both, and, most remarkably, the arabinopyranosyl
system has a pairing strength that is unprecedented in any known oligonucleotide
system, natural or artificial (Fig. 1).
complete base-pairing promiscuity exists among the 4 pentopyranosyl systems;
all 4 cross-pair efficiently with each other.
The observations made so far clearly point to the conclusion that Nature
did not select a genetic system on the basis of the criterion of maximal base-pairing
strength. The search for the relevance of other selection criteria, such as the
potential of a system 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 the natural nucleic acids themselves.
Chemistry of Pyranosyl-Rna
Pyranosyl-RNA, the nucleic acid alternative that consists of the same building
blocks as RNA, is the alternative studied most extensively. Most recently, we
correlated interstrand base stacking and duplex properties, such as thermal duplex
stability, effect of dangling bases on duplex stability, and circular dichroism
spectral properties. The 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 backbone inclination to be
a useful parameter for the structural classification of oligonucleotide duplexes.
A hypothetical chemical property of pyranosyl-RNA related to interstrand base
stacking is the mediation of a peptide synthesis through preorganization of pyranosyl-RNA--bound α-amino
acid building blocks on a pyranosyl-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. Using amido-triphosphate,
a phosphorylating agent derived from metatriphosphate by reaction with ammonia,
we showed the existence of a strictly regioselective phosphorylation of the α-position
of aldosugars (glycolaldehyde, glyceraldehyde, threose and erythrose, ribose,
arabinose, xylose and lyxose) under mild reaction conditions. 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 are potentially of prebiotic significance
and is expected to open a new pathway for the formation of mononucleotides.
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,
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.