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Scientific Report 2008


Chemistry




Chemical Etiology of Nucleic Acid Structure


A. Eschenmoser, R. Krishnamurthy, G.K. Mittapalli, R.R. Kondreddi, Y. Osornio, V.S. Naidu

In the general context of our project to map the landscape of potentially primordial informational oligomer systems, we have been working during the past year on the following topics.

Oligomers Based on 5-Aminopyrimidine—Tagged 2′→3′-Phosphodiester—Linked Glyceric Acid Backbones

We have undertaken the synthesis and study of the base-pairing properties of oligomers derived from a 2′,3′-phosphodiester—linked glyceric acid backbone that has 2,4-disubsituted 5-aminopyrimidines, attached to the carboxyl group of glyceric acid via an amide bond at the 5-amino group, as recognition elements (Fig. 1). The structure of this oligomeric system is based on a structural simplification of the oligonucleotides containing lyxopyranosyl (2′→4′)— and threofuranosyl (2′→3′)—linked phosphodiester backbones, which we studied previously. Among the oligomer systems depicted in Figure 1, the nucleic acid derived from the glycerol backbone is not considered to be a potentially prebiotic system, in contrast to the oligomer system derived from glyceric acid and tagged via amide bonds with 5-aminopyrimidines.
Fig. 1. Structural simplification of α-L-threofuranosyl-(3′→2′) nucleic acid, which was inspired by studies on (3′→4′)-lyxopyranosyl nucleic acid, gives rise to acyclic informational oligomeric systems. Two examples are shown: glycerol nucleic acid and glyceric acid nucleic acid.


We have completed the synthesis of such a glyceric acid—derived oligomer containing six 5-aminouracil units (6-mer) and have studied its base-pairing properties with DNA, RNA, and α-L-threofuranosyl-(3′→2′) nucleic acid. Base pairing was strong between the
6-mer and poly(dA) (Fig. 2), was somewhat weaker with the corresponding poly(rA), and even occurred with α-L-threofuranosyl-(3′→2′) nucleic acid. We are expanding the study to include the complementary partner strand tagged with 2,4,5-triaminopyrimidine and have explored different pathways for synthesizing the suitably protected building blocks necessary for the automated oligonucleotide synthesis.

Fig. 1. Structural simplification of α-L-threofuranosyl-(3′→2′) nucleic acid, which was inspired by studies on (3′→4′)-lyxopyranosyl nucleic acid, gives rise to acyclic informational oligomeric systems. Two examples are shown: glycerol nucleic acid and glyceric acid nucleic acid.

Fig. 2. UV (left) and circular dichroism (right) spectroscopic data for base pairing between 5-aminouracil—tagged 2-phosphoglycerate hexamer and DNA, poly(dA); c = 5+5 μM. Measurements were made in phosphate buffer.


Synthesis of Oligodipeptides of Aspartyl-3-Aminoalanine Dipeptide Tagged with Orotic Acid

In our search for alternative heterocycles that would be potentially prebiotic and offer opportunities for becoming chemoselectively attached to a backbone, we considered orotic acid as a candidate. Orotic acid and its 5-substituted derivatives have been identified as products from the hydrolysis of polymeric material formed from hydrogen cyanide. In addition, the involvement of orotic acid as a nucleobase in the biosynthetic assembly of pyrimidine nucleotides justifies and warrants exploration of its base-pairing properties. We are synthesizing the necessary building blocks for the synthesis and study of the base-pairing properties of oligomers consisting of aspartyl-3-aminoalanine dipeptide units tagged with orotic acid (Fig. 3). The choice of the oligodipeptide backbone on which orotic acid would be attached was influenced by the results of our previous studies. Because the carboxyl group is now on the heterocycle, amide bond—mediated tagging of the carboxyl group of orotic acid requires a 3-aminoalanine as a tagging unit.
Fig. 3. Orotic acid as a recognition element. Also shown is the oligodipeptide tagged with orotic acid.


Exploring the Chemistry of Glyoxylate and Dihydroxyfumarate

A research project such as mapping the landscape of potentially primordial informational oligomer systems eventually demands the conception of, and the commitment to, a detailed chemical scenario for the type of organic chemistry that is supposed to have led to such oligomers under primordial conditions. Figure 4 depicts the chemical nature of the scenario we have decided to study experimentally. In the reaction cycle shown, glyoxylate would autocatalytically convert itself into its dimer dihydroxyfumarate. Dihydroxyfumarate is a known compound that we postulate can act as a common starting material for a large variety of biomolecules, such as sugars, α-amino acids, and pyrimidines, and for other organics of etiologic interest by reactions that are essentially unexplored thus far but are deemed compatible with the constraints of a primordial chemistry. We are conducting exploratory studies for assessing the chemistry of selected intermediates postulated to be formed from the chemistry of glyoxylate and dihydroxyfumarate. Some of the preliminary results are encouraging.
Fig. 4. Hypothetical autocatalytic cycle for the dimerization of glyoxylate to dihydroxyfumarate and the biomolecules to be derived from the constituents of that cycle.


Publications

Eschenmoser, A. On a hypothetical generational relationship between HCN and constituents of the reductive citric acid cycle. Chem. Biodivers. 4:554, 2007.

Eschenmoser, A. The search for the chemistry of life's origin. Tetrahedron 63:12821, 2007.

Koch, K., Schweizer, B., Eschenmoser. A. Reactions of the HCN-tetramer with aldehydes. Chem. Biodivers. 4:541, 2007.

 

Albert Eschenmoser, Ph.D.
Professor

Ramanarayanan Krishnamurthy, Ph.D.
Associate Professor



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