Newly Discovered Protein Fold Exhibits Novel Biochemistry, Potential as Future Drug

Dr. Mydy, a postdoctoral research fellow in the Department of Medicinal Chemistry, studied the biosynthesis of a class of macrocyclic peptides found in plants with potential use as therapeutic drugs. She identified a fascinating new protein fold that “has a really unusual mechanism to form cyclic peptides. It is new biochemistry that we have not seen before,” Dr. Mydy said. 

The discovery sparked some excitement in the field and was published in Nature Chemical Biology on February 14, 2024. “There was no experimental information on our protein, known as AhyBURP. The only hint we had for function was that the protein needed copper to cyclize a peptide,” she noted.

Found in the roots of the peanut plant, the peptide cyclase AhyBURP is a representative of the founding Unknown Seed Protein (USP)-type, which in turn is part of the BURP-domain protein family.

Studying the protein with X-ray crystallography using the Advanced Photon Source at Argonne National Laboratory, Dr. Mydy and the team found that the protein binds copper near the peptide, which is cyclized. “The protein, AhyBURP, uses copper and oxygen in a unique way that we’re still investigating. Most cyclic peptides need another enzyme to come in and do the cyclization chemistry; however, AhyBURP can do it within the same protein on itself.” (Fig.1)

“Other copper-dependent proteins function by attaching oxygen somewhere on the peptide. We don’t observe that, and we want to know why. I see this as the first example of this type of chemistry that can happen with copper and oxygen within a protein,” states Dr. Mydy.

The discovery of this new protein grew from ongoing work in the lab of Roland Kersten, assistant professor of chemistry at the College of Pharmacy. As part of the U-M Natural Product Discovery Initiative, the Kersten lab aims to discover and research new plant-based chemicals in this field that can be turned into drugs and ultimately cure human diseases. “We use a modern approach where we screen the genetic sequences of plants, searching for genes connected to new chemistry,” Dr. Kersten said. “That’s how we identified the cyclic peptide products and their underlying proteins as a target of interest.”

This class of peptides is of interest because their cyclization properties make them more structured and stable, increasing their potential to be used as drugs. Many drugs, including chemicals derived from living organisms, are cyclic, meaning that they can bind drug targets and remain intact in a patient for a desired time. Nature has evolved many biochemical solutions to produce such cyclic molecules. 

Dr. Kersten has isolated other compounds made by the same protein family that have been shown to have suppressing effects on lung cancer cells in lab tests, so there is hope that this discovery will have potential as an anti-cancer agent in the future. 

“Now that we know what the protein looks like for one of the BURP-domain proteins, we can test more ideas about how the protein may influence the chemical reaction between the peptide, copper, and oxygen to form cyclic peptides,” Dr. Mydy said.

A structural biologist and enzymologist by training, Dr. Mydy is excited about her discovery. “It is a fantastic and challenging puzzle to figure out why this is happening and understand the structure,” Dr. Mydy said. “It’s extremely exciting to have found a new protein fold. This type of discovery doesn’t happen too often”.