Radical SAMs, Microscopic Lassos, Protein Dynamite—on the Wild Frontier of Enzyme Engineering

If you’ve been on a prescription medication, you might have wondered why prescription drugs are so expensive.

Finding a drug that treats a condition effectively without causing serious side effects requires an enormous number of research hours, as well as large amounts of expensive chemicals.

And not only is the process of making drugs costly and time-consuming, it often creates toxic and wasteful by-products that impact the environment.

A new strategy called green chemistry has emerged in the last eight years that has revolutionized the field of pharmaceutical engineering. Instead of reacting chemicals together to make a medication, drug engineers now use enzymes, which are small molecular machines that can make the right drug compound without any by-products.

BYU is making exciting developments in the field of green chemistry. Dr. James Moody of the Chemistry and Biochemistry Department is mentoring students in the creation of a type of enzymes called radical SAMs that are designed for use in drug development.

SAM stands for S-adenosylmethionine, which refers to a particular arrangement of atoms in an enzyme that can do some powerful chemistry.

“Radicals are kind of like dynamite in the protein world,” explained Moody. “Dynamite can be useful if controlled.”

Radical SAMS are oxygen-sensitive, which makes them difficult to work with because they need to be handled in an oxygen-free environment. However, they can cause useful reactions that other enzymes can’t.

“No one has [engineered drugs] using these radical SAM enzymes. “[By creating enzymes with radical SAMs], we’re adding dynamite to the table,” said Moody.

That’s not all the Moody lab is adding to the table. In order to efficiently engineer enzymes, researchers need high-resolution pictures of the proteins they are working with. Having a good picture of a diseased protein can help researchers quickly find where the mutation is on the protein. It also allows them to enter the picture into computer software that finds effective drug matches.

There is a problem though. “Proteins are awfully wiggly,” said Moody.

“A good example of this is if you are taking a wedding picture with your whole family, and you’ve got your two-year-old nephew who doesn’t want to sit still. You get the picture back and he’s a blur in the middle because he’s moving too quickly. But if you could get someone to hold him down, then he might not be a blur in your picture.”

Like a two-year-old nephew, proteins don’t like to sit still enough to have their picture taken. They also don’t like packing together into crystals. Moody’s lab has been working to make protein chaperones, which function like the family member that holds the wiggly two-year-old in place. The protein of interest, along with the protein chaperone, are grown within bacteria and crystallized; then the crystal is fished out with microscopic lassos. This process makes it possible to take pictures of previously unseen proteins, as well as significantly reduce the cost of making an image—which in the past cost about $20,000 per protein.

Moody and his team hope that BYU’s contributions to the pharmaceutical field— which include their development of powerful enzymes and efficient imaging methods—will lower the cost of prescription drugs in the future.

—Lia Ludlam, College of Physical and Mathematical Sciences

By Angela Cava and Lia Ludlam Posted on