DNA Gets a Chemistry Lesson

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Robert F. Service
1998-11-02 19:30
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Scientists have found a way to make DNA an active, versatile player in chemistry. Experts says the discovery, reported in the current Angewandte Chemie International Edition in English, will lead to the development of a new family of DNA-based enzymes capable of performing new chemical reactions that could be useful in synthesizing new drugs, among other things.

Although DNA contains the instructions for building and maintaining cells, the genetic material doesn't have an active hand in stirring up chemical reactions. Unlike proteins--the active players in biochemistry--DNA lacks chemically active groups of atoms dangling from its building blocks. To enliven the molecule, molecular biologists Carlos Barbas III and Kandasamy Sakthivel of the Scripps Research Institute in La Jolla, California, decorated DNA building blocks, or nucleotides, with chemically reactive groups, such as the amino acid components of proteins. Such modified nucleotides are relatively easy to synthesize and incorporate in DNA strands. But doing useful chemistry would require multiple copes of the modified DNA. And DNA duplicating enzymes, known as polymerases, are finicky and refuse to copy modified DNA strands.

Barbas and Sakthivel knew that when DNA's nucleotides assemble into their characteristic double helix, they always turn the same face to the nucleotide partner to which they bind. And they thought that if they made their changes on the opposite--outward facing--portion of the molecules, the changes might not sabotage this pairing or the copying efforts of polymerases. The strategy worked. After only three tries, they engineered a thymidine nucleotide with a rigid arm attached to the back that was readily incorporated into DNA chains, which DNA polymerases could then duplicate ad infinitum.

The new work is "very exciting" says Bruce Eaton, a nucleic acid catalysis expert at NeXstar Pharmaceuticals in Boulder, Colorado, because researchers have already come up with ways to coax polymerases to make a few random mistakes in their copying efforts, in the process turning out trillions of DNA strands that all differ slightly from one another. Do that with DNA studded with added functional groups, says Eaton, and you might end up with a variety of unexpected chemical properties. "There's a chance to evolve new chemistries no one has ever seen before."

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