Teamwork beats going it alone when it comes to making from scratch at least one complex carbohydrate that could be the basis for new drugs. Two bacterial enzymes tethered to each other can efficiently produce a carbohydrate whose synthesis had long stymied chemists. The tandem enzymes, described in the August Nature Biotechnology, could remove a technical hurdle for companies hoping to make a dietary supplement for infants and potential drugs for blocking inflammation.
Carbohydrates, or chains of sugars, help cells recognize and stick to each other with exquisite specificity because they can assume many different configurations. But that same attribute makes them hard to synthesize. Carbohydrates composed partly of sialic acid--long sought as potential inhibitors of inflammation because they could jam cell-to-cell communication--have been especially tricky to make. Scientists have tried to use solutions of bacterial enzymes to synthesize the compounds in the lab, but the yields have been poor, says study co-author N. Martin Young of the National Research Council (NRC) in Ottawa, Canada.
To try to make the reaction more efficient, the NRC team linked two enzymes from the bacterium Neisseria meningitidis with a short chain of amino acids. The linked enzymes act as a mini assembly line--the first enzyme makes sialic acid chemically reactive and passes it to the second enzyme, which attaches sialic acid to an existing carbohydrate, such as lactose. In lab trials, more than 90% of the lactose was converted to sialyl lactose in minutes--fast enough to spur co-author Robert Bayer and his colleagues at Cytel Corp. in San Diego to try to scale up production. The large-scale reaction worked, and Cytel is now using the linked enzymes to make up to 15 kilograms of sialyl lactose, a component of breast milk that the company hopes to sell as an additive for infant formula.
Other experts like the idea of fusing the enzymes. "It's an interesting trick," says glycobiologist Ajit Varki of the University of California, San Diego. Carbohydrate chemist Y.C. Lee of Johns Hopkins University says the new fusion enzyme may also make it feasible to produce sought after carbohydrates like sialyl-Lex, which coats the surface of cells and might be especially useful for fighting inflammation.