Non-Standard Amino Acids Create More Effective Proteins

"Unnatural" amino acids can make proteins 30 times more effective in treating cancer, a new study finds.

The study authors say the discovery might open the door to more experiments with novel amino-acid compounds, possibly creating drugs that work more effectively and with fewer side effects.

About 20 amino acids are normally used by all life on Earth as the building blocks for proteins, but in fact a vast number of other amino acids exist.

By using these "unnatural" amino acids to build proteins, "we have access to many more shapes and charges as compared to nature," researcher Ryan Mehl, a biochemist at Franklin and Marshall College in Lancaster, Pa., told LiveScience.

For the first time, an unnatural amino acid was shown to have improved the activity of an enzyme, a type of protein which catalyzes chemical reactions and is essential to life's activities.

Mehl and his colleagues experimented with the enzyme nitroreductase, which helps activate cancer-therapy drugs.

One amino acid within nitroreductase is key to binding the enzyme to the drugs it activates.

The researchers experimented with replacing this amino acid with all the other natural ones -- and eight unnatural ones. The resulting enzyme variants were generated by bacterial cells in lab dishes.

Substitution of one unnatural amino acid created a nitroreductase variant that was more than 30 times more efficient than normal.

It was also more than twice as good as the best variant that used a replacement natural amino acid.

The discovery might mean that patients in the future could use reduced amounts of cancer drugs, which often have dangerous side effects.

Commercial-scale manufacture of "unnatural" enzymes should be feasible in the near future, Mehl said.

He and his colleagues reported their findings in the Journal of the American Chemical Society.

"We can improve upon nature by working with only one site," Mehl said. "Just imagine the potential of using these amino acids throughout a protein or organism."

"Evolving a whole protein instead of one site will be technically challenging but is currently feasible," he said, but cautioned that "evolving unnatural organisms in a convincing way might be a couple years off."

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