Enzyme disables excess amino acid

Phenylalanine, an amino acid that is essential to the body, requires precise control. Children who get too little phenylalanine in their diet fail to grow properly. Retaining too much can cause brain damage. Most people can dispose of any surplus phenylalanine, but those with a genetic disorder called phenylketonuria (PKU) lack the enzyme that breaks down the excess.

 Scientists have now engineered bacteria to produce an enzyme that might replace the one PKU patients lack. In the March 2 Proceedings of the National Academy of Sciences, researchers report that injections of the enzyme reduced blood concentrations of phenylalanine by roughly half in a dozen mice unable to break down the amino acid. The scientists then achieved similar results by giving the mice the substitute enzyme in food, says study coauthor Charles R. Scriver, a geneticist and pediatrician at Montreal Children's Hospital and McGill University.

 A half century ago, scientists were thrilled to discover that the neurological risks of PKU could be avoided if children adhered to a diet devoid of meat, fish, dairy products, breads, nuts, and many other foods. Maintaining such a diet is difficult, however, and PKU children also must consume an unpleasant-tasting food additive to get adequate protein.

 To develop an alternative approach, the scientists added a yeast gene to Escherichia coli bacteria. The E. coli then manufactured an enzyme that breaks down phenylalanine in a simpler manner than the process directed by its human counterpart.

"How to move forward with clinical development of the enzyme is still a question," says study coauthor Robert Heft, a molecular biologist and president of IBEX Technologies in Montreal. "The mice data predict a dose which would be too high in humans to be commercially feasible." The researchers also don't know whether effective concentrations of the enzyme could have harmful side effects, he says.

 Moreover, the substitute enzyme "might be seen by the human body as a foreign body . . . and might induce immunoreactivity," says Harvey L. Levy of Children's Hospital in Boston.

 The genetic disorder affects roughly 1 in 12,000 babies born in North America. For 35 years, U.S. newborns have been screened for PKU. Those with the enzyme deficiency are put on the special diet. Once PKU patients reach adolescence, some go off the diet with few ill effects, Scriver says. However, some adults with PKU begin to lose the ability to concentrate well, have trouble planning, and may even show short-term memory loss, he adds.