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ChEM-H researchers develop a new way to probe metabolic molecules

Jonathan Long
Oct 3 2019

A vast number of enzymes in our bodies remain mysterious, their biochemical and physiological functions unknown. Now, Stanford ChEM-H researchers have developed a method for rapidly filling in animals’ biochemical maps and, in the process, identified the function of a previously mysterious enzyme linked to cardiometabolic disease.

By Nathan Collins

The new study, published October 3 in Cell Chemical Biology, is the first publication from the lab of Jonathan Long, an assistant professor of pathology and a faculty fellow of ChEM-H who focuses on mammalian metabolism.

Part of the motivation for the research, Long said, is the great many molecules related to metabolism in animals’ bodies that biochemists know are there but can’t connect to any particular biological function. “We understand less than half” of those molecules, Long said. “There’s a lot of biochemical space that’s undiscovered.”

The other motivation was Long and his lab’s interest in metabolism, which led the lab to focus their attention on the M20 peptidase family of enzymes. Some forms of those enzymes, Long said, have been linked to heart disease, diabetes and obesity, yet the nature of those links isn’t always clear. Researchers don’t even know what one enzyme, dubbed CNDP2, does in the rich network of chemical reactions that drive metabolism – if anything at all.

Most of the solutions to those problems have encountered roadblocks of their own. Studying metabolism in live mice, for example, is slow because of the time it takes to breed genetically distinct mice. Research in isolated cells are faster, but it’s hard to say whether the results would generalize to the more complicated biological environment of a living animal.

To start to address those issues, Long and colleagues built a series of adeno-associated viruses designed to express the five enzymes in the M20 family, then injected each one them into three live mice. There, the idea was, they’d create an oversupply of the enzyme, modifying each mouse’s metabolism and, therefore, the abundance of a variety of molecules – known and unknown – in the mice.

With help from ChEM-H’s Metabolic Chemistry Knowledge Center, the team both confirmed the role some M20 enzymes play and discovered that CNDP2 – the enzyme that had no known function – helps process a metabolite called Thr-Thr, which had not previously been known to be part of mammals’ metabolism.

The work therefore uncovers a new biochemical pathway and provides a foundation for studying the functions of CNDP2 and Thr-Thr, Long said. In the long run, those results and others like them could help biochemists and doctors better understand a variety of diseases.

“What we’re trying to do is to bring some insight into how molecules in these metabolic pathways are linked to outcomes like obesity or diabetes,” Long said. “By understanding those biochemical mechanisms, maybe we can find ways of better understanding or eventually treating cardiometabolic disorders.”