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Angewandte Chemie International Edition
Press-Release No. 19/98
Angew. Chem. Int. Ed. 1998, 37 (20), 2872 - 2875

When Four Letters Are Not Enough:
Chemists expand the DNA alphabet in order to build protein-like DNA enzymes

Would Marcel Proust have been able to write "In Search of Lost Time" with only 4 letters available to him? Carlos F. Barbas III and Kandasamy Sakthivel from the Californian Scripps Research Institute have had a good look at a similar question. They have added to the four letters making up the simple chemical alphabet of deoxyribonucleic acid (DNA) - the molecule in which the genetic information of all higher forms of life is written. However, the purpose of the work was not to create some kind of 'super' life-form, but rather to make DNA derivatives that would be able to carry out various chemical processes in the laboratory in one go, rather like "natural" enzymes.

In nature, chemical reactions in living organisms are controlled by specific proteins, known as enzymes. All enzymes are made up of combinations of twenty building-blocks - the amino-acids. This variety of components is essential to allow cells to build enzymes designed for particular chemical tasks. The process could be likened to model building from a box of bricks: far more realistic models can be built from a set containing arches, cubes, and cones than from a set with only right-angled bricks.

In the past few years, it has been discovered that DNA can also control certain chemical reactions. This is especially interesting as the PCR method, which can be used for reproducing in great quantities even the tiniest amount of DNA on demand, is already available as an elegant and tried and tested way of producing new DNA enzymes. Unfortunately DNA consists of only four building-blocks - a somewhat limited set of bricks - which greatly restricts the fertile imagination of the chemist for DNA modeling. Thus, researchers must increase the number of DNA components they have to work with in order to produce more complex DNA enzymes. But there is also the added restriction that the new building-blocks must be suitable for duplication by the PCR process, which is actually designed for naturally occurring genetic material.

Barbas and Sakthivel have now solved this problem for the first time, not by starting from scratch, but by modifying a natural section of DNA with a variety of short chain molecules. These units stick out slightly from the main DNA chain; this means that they do not interfere with the PCR process. The ends of the novel side-chains carry charged building-blocks, which chemists might be able to use in the future to build up DNA enzymes, which are every bit as good as 'true' enzymes.

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