Proof that proteins can be custom-designed

Ever since the advent of recombinant-DNA technology, scientists have conceived that it will be feasible to create entirely new enzymes for specific needs. In an article in today’s issue of the journal Science, researchers from Uppsala and Korea present concrete proof of this. They have succeeded in converting an enzyme involved in normal human metabolism into an enzyme that is custom-designed to break down a specific substance, cefotaxime.

“The product in this case is not the main point, but we have shown that it is possible to totally transform an enzyme for a new and pre-determined activity. We have succeeded by using a rational reconstruction of the enzyme’s active site in combination with directed molecular evolution in test tubes,” says Professor Bengt Mannervik, at the Department of Biochemistry and Organic Chemistry, who planned the study.

In the cells of all organisms, proteins are involved in molecular functions of highly disparate types: as receptors of light and smells, for transmission of signals, mechanical work, control of the function of genes, and the synthesis and degradation of chemical substances. Despite all of these diverse functions, only an insignificant number of all imaginable protein structures ever come to existence in living cells. With the help of recombinant-DNA technology and chemical modifications scientists around the world are therefore trying to produce entirely new proteins that can be used for biotechnological applications in medicine, the drug industry, forestry and agriculture, and the production of foodstuffs. However, researchers have had to look for proteins at random after reconstructions, like a needle in a haystack.

Bengt Mannervik and his research team at Uppsala University, in collaboration with Hak-Sun Kim’s research team in Korea, have converted an enzyme in human cells that participates in normal metabolism into an enzyme that degrades cefotaxime, an antibiotic similar to penicillin. The human enzyme was complemented with parts from the bacterial enzyme beta-lactamase, which bacteria use to break down antibiotics of the penicillin type. The scientists then managed to isolate bacteria with the new enzyme and to show that they enhanced their capacity to survive by degrading cefotaxime.

“The study shows that it is possible to drastically alter the properties of a natural protein and that an enzyme’s functions can be custom-designed for new uses,” says Bengt Mannervik.