New plant protein may help develop anti-cancer drugs

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University of Michigan researchers have made a groundbreaking discovery in plant biochemistry, unveiling a new mechanism that plants use to create cyclic peptides—molecules with significant potential for pharmaceutical development.

Cyclic peptides are especially valuable because they can bind to drug targets that are typically challenging for other molecules, making them a hot topic in the search for new medicines.

The study, spearheaded by Lisa Mydy and Roland Kersten from the U-M College of Pharmacy, was published in the prestigious journal Nature Chemical Biology.

This research marks the first identification of a unique plant protein structure capable of generating cyclic peptides, including one with promising anti-cancer properties.

Mydy, a postdoctoral research fellow in the Department of Medicinal Chemistry, expressed her excitement over the discovery, noting the rarity of uncovering such novel biochemistry.

The team focused on a class of macrocyclic peptides known for their therapeutic potential and discovered an entirely new protein fold that facilitates the formation of these cyclic peptides in a manner previously unseen in nature.

The protein in question, named AhyBURP, was found in the roots of the peanut plant. It belongs to the Unknown Seed Protein (USP) type within the BURP-domain protein family.

What makes AhyBURP remarkable is its use of copper and oxygen to cyclize peptides without the need for another enzyme—a process distinct from other known copper-dependent proteins.

This discovery was facilitated by advanced techniques such as X-ray crystallography, conducted with the help of the Advanced Photon Source at Argonne National Laboratory.

The research team’s findings suggest that AhyBURP represents a new form of chemistry involving copper and oxygen within a protein, opening up new avenues for understanding how cyclic peptides are formed in nature.

The implications of this discovery extend beyond the academic world into the realm of pharmaceutical development. Cyclic peptides are structurally stable and can effectively bind to their targets, making them ideal candidates for drug development.

Kersten’s lab, as part of the U-M Natural Product Discovery Initiative, is dedicated to identifying new plant-based chemicals with the potential to become therapeutic drugs.

The discovery of AhyBURP and its unique mechanism offers hope for the development of new treatments, including potential anti-cancer therapies.

Kersten highlighted the modern approach of screening genetic sequences of plants to uncover genes linked to novel chemistry, leading to the identification of cyclic peptide products and their associated proteins.

The research team is optimistic about the therapeutic potential of this class of peptides, particularly given the isolation of other compounds by the same protein family that have shown efficacy against lung cancer cells in laboratory tests.

This discovery not only enriches our understanding of plant biochemistry but also paves the way for the development of new, more effective pharmaceuticals.

The researchers are excited to delve deeper into the structural biology and enzymology of AhyBURP, unraveling the intricate puzzle of how this protein interacts with copper and oxygen to create cyclic peptides.

This breakthrough is a testament to the potential of plant biochemistry to contribute to medical science, promising advancements in the treatment of various diseases.

The research findings can be found in Nature Chemical Biology.

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