Building new proteins with odd parts.

Building new proteins with odd parts

With a palette of 20 or so amino acids, cells assemble the proteins they need. Scientists can modify these proteins by substituting one naturally occurring amino acid for another. Now they are finding ways of inserting unusual amino acids into their designs in hopes of endowing proteins with otherwise unavailable chemical features. The payoffs might include new drugs, industrial enzymes or molecular tools for basic biochemical research.

Building on work by others, chemist A. Richard Chamberlin of the University of California, Irvine, and his co-workers are using an innovative technique to plug exotic amino acids into specific protein sites. They report their latest efforts in the Sept. 27 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY.

To make a protein, a cell transcribes segments of its DNA into messenger RNA (mRNA), which carries the code to protein-assembling organelles called ribosomes. The mRNA then directs protein assembly by sequentially attracting specific transfer RNA (tRNA) molecules, each of which carries one of the 20 natural amino acids.

To install a non-natural amino acid into a polypeptide, or protein fragment, Chamberlin's group first replaces a short DNA fragment (codon), which translates into an amino acid with a termination codon, which normally stops protein assembly in the ribosome because it has no associated tRNA or amino acid. By attaching a synthetic variation of the amino acid tyrosine to a lab-made tRNA molecule that sticks to the termination codon, the researchers can slip the modified amino acid into a polypeptide.

In the April 14 SCIENCE, other researchers reported using a similar technique to insert amino-acid analogs into the enzyme beta-lactamase.

Chemist Sidney M. Hecht of the University of Virginia in Charlottesville, who laid much of the chemical groundwork for the new technique, says he hopes to extend it to even odder amino acids for added flexibility in protein design.