04:20am Sunday 31 May 2020

Scientists Find Complex Switch Regulates Simple Bodily Function

The enzyme carnitine palmitoyltransferase 1A (CPT1) is a common target for drugs that treat metabolic diseases like diabetes and obesity. Understanding how it works can help lead to better management of those diseases.

The team’s research was selected as a “Paper of the Week” by The Journal of Biological Chemistry, which means it is among the year’s top 1 percent of manuscripts reviewed by the journal’s editorial board in significance and overall importance.

Only 100 papers are selected from more than 6,600 published in the journal each year. The paper will appear in the Dec. 9 issue of the peer-reviewed journal.

Using nuclear magnetic resonance (NMR) spectroscopy, the USC team found that the regulatory domain of CPT1 acts like a switch, integrating three pieces of information to decide whether fatty acids will be stored or used. The enzyme takes into consideration its location on the membrane, the organism’s long-term metabolic state (starvation or famine) and the organism’s short-term metabolic state (whether it recently has eaten).

“That level of regulatory sophistication for an enzyme residing at the membrane-water interface is novel,” said Tobias S. Ulmer, the study’s principal investigator and an associate professor in the Department of Biochemistry and Molecular Biology at the Keck School-affiliated Zilkha Neurogenetic Institute. “It shows that those enzymes can consider several metabolic parameters to decide what they are going to do. It highlights the pivotal nature of the relatively simple chemical reaction that the enzyme regulates.”

The enzyme has a variant that is specific to the brain, which scientists want to study further, Ulmer said. Better understanding of the enzyme’s structure and membrane interactions ultimately could lead to better drugs for curbing appetite and treating obesity, he added.

Co-authors included Jampani N. Rao of USC and Gemma Z. L. Warren, Sara Estolt-Povedano and Victor A. Zammit of the University of Warwick in the United Kingdom. Funding was provided by the USC Liver Center, the National Institutes of Health and the British Heart Foundation.

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