Scientists at the Van Andel Research Institute have developed a novel biochemical platform to research a family of enzymes that are promising targets for cancer treatment.

The study (“A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity”), published in Science Advances, describes a new method that provides a high-resolution view of how these enzymes, lysine methyltransferases, selectively mark proteins with chemical tags that alter their function. Because of their central role in all aspects of health and disease, proteins and the molecules that edit and interact with them often are targets for therapeutic development.

The platform was developed by Van Andel Research Institute’s Scott Rothbart, Ph.D., in collaboration with EpiCypher.

“Lysine methylation is a key regulator of histone protein function. Beyond histones, few connections have been made to the enzymes responsible for the deposition of these posttranslational modifications. Here, we debut a high-throughput functional proteomics platform that maps the sequence determinants of lysine methyltransferase (KMT) substrate selectivity without a priori knowledge of a substrate or target proteome. We demonstrate the predictive power of this approach for identifying KMT substrates, generating scaffolds for inhibitor design, and predicting the impact of missense mutations on lysine methylation signaling,” write the investigators.

“By comparing KMT selectivity profiles to available lysine methylome datasets, we reveal a disconnect between preferred KMT substrates and the ability to detect these motifs using standard mass spectrometry pipelines. Collectively, our studies validate the use of this platform for guiding the study of lysine methylation signaling and suggest that substantial gaps exist in proteome-wide curation of lysine methylomes.”

“This technology helps us to determine protein interaction networks for this understudied enzyme family based on chemical tagging,” said Dr. Rothbart. “Several inhibitors of these enzymes are currently in the clinical development pipeline for cancer therapy. Defining the spectrum of their activity is critical for understanding exactly how these drugs work and for selecting reliable biomarkers to track their activity in patients.”

Using their new technique, the team found that many more proteins may be tagged by lysine methylation than previously thought.

“Our study suggests that what we currently know about lysine methylation is just the tip of the iceberg,” said Evan Cornett, Ph.D., the study’s first author and a postdoctoral fellow in Dr. Rothbart’s laboratory at the Institute. “The method we developed will allow us to identify new targets across the full set of lysine methyltransferases in humans and, in doing so, help us and others determine which cancers and other diseases could benefit from treatments targeting this class of enzymes.”

“The beauty of this technology is its simplicity and throughput, which is staggering compared to current mass spectrometry-based approaches,” said Martis Cowles, Ph.D., EpiCypher’s CBO and study co-author. “We are excited to use this technology to help drug developers identify new therapeutic targets and even identify optimal target substrates for high-throughput inhibitor screening.”

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