Molecular mechanisms of fatty acid activation and utilization

• Applicant: Professor Dr. Florian Fröhlich
• Subject Area: Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567762489

Fatty acids (FAs) are the building blocks of many lipids in cells. FAs can vary in their length and in their degree of saturation. To be utilized by lipid metabolic enzymes, FAs need to be activated by the formation of a thioester between their carboxyl group and coenzyme A. This reaction is catalyzed by FA-CoA synthetases. However, very little is known about the biophysical behavior of activated and non-activated FAs in membranes. It remains unclear whether activated fatty acids reach the catalytic centers of enzymes from the cytosol or from the membrane. In this project, we will elucidate the molecular mechanisms of fatty acid activation and utilization in cells. First, we will use a combination of molecular dynamics simulations and biochemical approaches to elucidate the mechanism of very long-chain fatty acid (VLCFA) activation by the yeast VLCFA CoA synthetase Fat1 and a mammalian counterpart, ACSL3. In a second step, we will use our method spectrum to determine how activated FAs reach the catalytic centers of two model lipid metabolism enzymes: the yeast serine palmitoyltransferase and the yeast ceramide synthase. For all our aims, we have strong preliminary data that allow us to propose these challenging experiments. Completion of these aims will shed light on the long-standing questions of whether FAs and their activated derivatives behave as membrane lipids, how they are activated, and how they reach the catalytic centers of metabolic enzymes. The fundamental insights we aim to uncover are essential for advancing our understanding of lipid biochemistry, ultimately informing drug design and therapeutic strategies to combat metabolic disorders and cancer.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Professor Dr. Stefano Vanni