Versatile enzyme

An unusually active enzyme might provide the key to synthesising a wide variety of potential pharmaceutical active ingredients, according to a team at the Salk Institute in California. The structure of the enzyme allows many different molecules to fit inside its active site, generating many different products.

The enzyme, named Orf2, catalyses the addition of the fat-like prenyl functional group to small aromatic molecules. This changes the biological activity of the aromatic group completely, allowing it to interact with many receptors in the body. ‘We actually have in our hands now the ability to do things that a chemist might not be able to do, or if a chemist was able to do it, it could be expensive and time-consuming,’ comments Joseph Noel, one of the research team.

The researchers were studying the prenylation of several aromatics, including flavonoids, the bitter compound in hops that is also used as an intermediate in sunscreen, pigment and antibiotic manufacture; and olivetol, a component of olive oil used to manufacture compounds such as THC. Most prenylation enzymes are specific to a single molecule or a very small group, but the Orl2 enzyme was able to attach prenyl groups to almost every aromatic tested. Some of the new hybrid molecules were identical to those found in nature, but some had never been seen before.

The reason the enzyme can perform this trick is that its active site, rather than being shaped to fit a single molecule like a lock for a specific key, is a wide, barrel-like structure, unlike any protein fold seen before. Moreover, the enzyme is obligingly easy to work with. ‘The big advantage that we have with our system is that it’s a small, soluble, easy-to-work-with bacterial protein,’ says researcher Stéphane Richard. ‘It’s a kind of short-cut — a way to bypass what is done already in nature, but for which we don’t have the tools that nature has.’