Simpler Than DNA

BIOCHEMISTRY

Chemists have stripped the nucleic acid down to its bare essentials and introduced the simplest DNA analog known (J. Am. Chem. Soc. 2005, 127, 4174).

Such a simple nucleic acid structure may have been early Earth's predecessor of today's more complex DNA and RNA, says Eric Meggers, an assistant professor of chemistry at the University of Pennsylvania. In addition, a simple nucleic acid backbone can significantly streamline the synthesis of DNA analogs commonly used as building blocks for new materials.

Glycol nucleic acid (GNA; shown, B = base)—the analog introduced by Meggers, postdoc Lilu Zhang, and collaborator Adam Peritz—has just three carbon atoms and one stereocenter in the backbone, as opposed to five carbon atoms and four stereocenters in RNA's backbone. Nucleic acid researchers have thought that a cyclic sugar must be present in a nucleic acid phosphodiester backbone to give it the conformational preorganization it needs to base-pair and form a stable duplex with an opposite strand, Meggers says. They now know that that's not true, he adds, because GNA has no cyclic sugar and still displays Watson-Crick base pairing.

Meggers' group became curious about the possibility of removing the ring completely when they saw reports by Albert Eschenmoser, currently at Scripps Research Institute, of analogs with sugars that differ markedly from those in DNA and RNA. One of them, called TNA, uses a tetrose sugar and has a connecting chain between phosphate groups that is one carbon atom shorter than that in DNA. If TNA works, Meggers' group thought, then maybe a nucleic acid with a simple glycol group connecting the phosphodiesters might work as well.

It does work and, surprisingly, is more stable than DNA or RNA in duplex form. Eschenmoser notes that the surprising duplex stability of GNA "significantly influences our views about the structural prerequisites of Watson-Crick pairing."

Like the structure, synthesis of GNA is simple. The route developed by Zhang starts with a chiral epoxide to which she adds a nucleophile—in this case, a nucleobase. This spurs the key step: a stereospecific ring opening of the epoxide. "When I started as a postdoc," Meggers says, "I spent six months making two nucleotides." GNA takes nowhere near that long, and Meggers and Zhang are convinced that GNA's simple synthesis makes it a powerful tool in nucleic acid research. Their laboratory has switched over to working exclusively with GNA backbones.

GNA's greatest significance might lie, however, more in the prebiotic past than in the future. It is a promising pre-RNA candidate partly because of its simple starting materials: "a glycerol derivative, which is an elementary offspring of a triose, and the nucleobases for which prebiological access is widely accepted," says Christian J. Leumann, a nucleic acid researcher at the University of Bern, in Switzerland.

"Why should nature not start with the simplest solution?" Meggers asks.