Plants metabolically engineered to produce new drugs

Scientists have been engineering new genes into plants for a number of years in an effort to expand on naturally occurring medicinal compounds. Now chemists at MIT have gone one step further, using an approach known as metabolic engineering to alter the series of reactions plants use to build new molecules, thereby enabling them to produce unnatural variants of their usual products.

Instead of adding a gene that codes for a novel protein, metabolic engineering deals with the series of reactions within cells to increase the production of a certain substance. By adding new genes for new enzymes it is possible to reshape the way the host organism builds new molecules. Most metabolic engineers use bacteria as their host organism, partly because their genes are easier to manipulate, but Associate Professor Sarah O’Connor was drawn to engineering plants.

O’Connor led a team that added bacterial genes to the periwinkle plant, enabling it to attach halogens such as chlorine or bromine to a class of compounds called alkaloids that the plant normally produces. Many alkaloids have pharmaceutical properties while halogens are often added to antibiotics and other drugs because they can make medicines more effective or last longer in the body.

The team’s primary target was vinblastine, an alkaloid commonly used to treat cancers such as Hodgkin’s lymphoma. O’Connor sees vinblastine and other drugs made by plants as scaffolds that can be modified in a variety of ways to enhance their effectiveness. With this in mind, the researchers engineered periwinkle root cells to express genes that code for enzymes that attach chlorine or bromine to vinblastine precursors and other alkaloids.

Since it’s much more rare for plants to generate halogenated compounds on their own and it’s difficult to synthesize them in a laboratory, the two new genes used by the researchers came from bacteria that naturally produce an enzyme called halgenase.

To make alkaloids, plants first convert an amino acid called tryptophan into tryptamine. After that initial step, about a dozen more reactions are required, and the plants can produce hundreds of different final products. In the new genetically engineered plants, halogenase attaches a chlorine (or bromine) atom to tryptamine. That halogen stays on the molecule throughout the synthesis.

In the future, the researchers hope to engineer full periwinkle plants to produce the novel compounds. They are also working on improving the overall yield of the synthesis, which is about 15 fold lower than the plant’s yield of naturally occurring alkaloids. One way to do that is to introduce the halogen further along in the process, said O’Connor.

The engineered periwinkle plants created by the MIT researchers are described in the November 3 online edition of Nature.