News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999
Chemical Etiology of the Structure of Nucleic Acids
A. Eschenmoser, R. Krishnamurthy, H. Wippo, O. Jungmann, M. Stanek, S. Guntha,
R. Kudick, H. Huynh, A. Luther
In its third year, research in our group focused on the following projects:
Pentopyranosyl-(4´→2´) Ol Igonucleotide Systems
We extended the synthesis of pentopyranosyl nucleic acid alternatives to l-(α)-arabino-
and l-(α)-lyxopyranosyl-(4´→2´) oligonucleotide systems
containing 4 canonical bases and found that guanine-cytosine pairing in these
systems is consistent with the conclusions drawn earlier from studies on adenine-thymine
We found promiscuous cross-pairing among all 4 members of the pentopyranosyl
family (Fig. 1). Nevertheless, systems in which the conformation of the phosphodiester
junction at the 4´ position (equatorial in ribo and xylo and axial in lyxo
and arabino) is the same have a preference for each other. No cross-pairing of
the pentopyranosyl-(4→2´) systems with RNA occurs. Conspicuously strong
self-pairing of sequences such as 4´-TATTTTAA-2´ and 4´-TTAAAATA-2´ occurs.
This finding indicates a pronounced tolerance to mismatches in the family of
(4´→2´)-pentopyranosyl nucleic acid alternatives.
We have included in our studies the l-α-lyxopyranosyl-(3´→4´)
oligonucleotide system in which the repetitive unit of the backbone contains
only 5 covalent bonds rather than the 6 bonds characteristic of the (4→2´)-pentopyranosyl
systems and of RNA. In sharp contrast to the d-ß-ribopyranosyl-(3´→4´)
system investigated earlier, the corresponding lyxopyranosyl system is a surprisingly
strong base-pairing system, one that even shows (weak) cross-pairing with DNA.
It is the first oligonucleotide system known with only 5 covalent bonds in the
backbone unit that has the property of base pairing. The explanation for this
special is the diaxial conformation of the (3→4´)-phosphodiester junction.
This finding promotes a revision of present views about the constitutional constraints
thought to determine the base-pairing capability of oligonucleotide systems.
Chemistry of Pyranosyl-RNA
In studies on the properties of the pyranosyl isomer of RNA (pyranosyl oligonucleotide),
we examined the relative incorporation of the monomers pyranosyl-guanosine, pyranosyl-guanosine-2´-phosphate,
and pyranosyl-guanosine-2´,3´-cyclophosphate into a single-unit gap
of a duplex containing a template strand and 2 primer strands; one of the primer
strands was activated at the single-unit gap site as 2´,3´-cyclophosphate.
The relative ease of monomer incorporation increases from the nonphosphorylated
monomer to the 2´-phosphate to the 2´,3´-cyclophosphate; the 2´,3´-cyclophosphate
monomer connects by 2 ligations the 2 primer sequences into a full template complement.
The template system used in these ligation reactions serves as a scaffold in
ongoing acyl migration studies.
Regioselective Phosphorylation of Aldosugars
We recently described the phosphorylation of glycolaldehyde by amidotriphosphate
to form glycolaldehyde phosphate. This regioselective phosphorylation is the
first example of a phosphorylation process now extensively studied in our laboratory.
In this process, the activated phosphorylating reagent is brought into the constitutional
neighborhood of the phosphorylation site by a transient attachment of the reagent
to the sugar carbonyl group. With this method, a strict regioselectivity in the
phosphorylation of the hydroxyl group of the sugar is achieved. We hypothesize
that this type of phosphorylation could have etiologic relevance.
Beier, M., Reck, F., Wagner, T., Krishnamurthy, R., Eschenmoser, A. Chemical
etiology of nucleic acid structure: Comparing pentopyranosyl-(2´→4´)
oligonucleotides with RNA. Science 283:699, 1999.
Krishnamurthy, R., Arrhenius, G., Eschenmoser, A. Formation of glycolaldehyde
phosphate from glycolaldehyde in aqueous solution. Origins Life Evol. Biosphere
Micura, R., Kudick, R., Pitsch, S., Eschenmoser, A. Opposite orientation
of backbone inclination in pyranosyl-RNA and homo-DNA correlates with opposite
directionality of duplex properties. Angew. Chem. Int. Ed. 38:680, 1999.