Carnitine palmitoyltransferase 1 is an enzyme in the outer mitochondrial membrane of mammals that is critical for metabolism. Researchers in the U.K. and U.S. now have shown how an important isoform of the enzyme, a potential target for several drug therapies, is regulated by environmental cues.
CPT1 controls the rate-limiting step in fatty acid β-oxidation. Because of the enzyme’s importance, CPT1A, one of the three isoforms of CPT1 found in several organs, presents a prime target for drug treatments. It is inhibited by malonyl-CoA, the first intermediate of fatty-acid synthesis and a signal for the short-term metabolic state of the mammal. The enzyme also is regulated by the curvature of the mitochondrial outer membrane. CPT1A also is sensitive to long-term nutrient levels or disease states, such as Type 2 diabetes or obesity, which change the fluidity and lipid composition of the outer membrane. But the question dogging researchers has been this: How does the enzyme take in these three different signals to control its function?
In a recent Journal of Biological Chemistry "Paper of the Week," Tobias S. Ulmer and colleagues at the University of Warwick in the U.K. and the University of Southern California showed that, depending on the malonyl-CoA concentration, membrane composition and curvature, CPT1A’s N-terminal regulatory domain adopted one of two structural states called Nα and Nβ. Nα inhibited the enzyme’s activity, but Nβ didn’t have an inhibitory effect. Nα:Nβ ratio set the enzyme’s sensitivity to malonyl-CoA.
Ulmer says it’s the first time that an on-off switch has been described for a membrane-bound protein that can integrate several environmental cues. Victor A. Zammit, one of Ulmer’s co-authors, emphasizes that the work can help the pharmaceutical industry in finding small molecules that “can affect the molecular switch in the direction in which the patient needs it.” For example, he says, drugs can be developed for those patients suffering from diabetic ketoacidosis, a condition when insufficient insulin causes the body to start breaking down fat, so the CPT1A is inhibited to oxidize fewer fatty acids. Alternatively, CPT1A could be activated with a drug to prevent fatty liver disease from developing, a condition that accompanies insulin resistance and diabetes.
Rajendrani Mukhopadhyay, Ph.D., (firstname.lastname@example.org) is the senior science writer for ASBMB Today and technical editor for JBC.