Biosynthesis of sterols and their role in membrane phase separation. Credit: Science Advances (2025). DOI: 10.1126/sciadv.adu7190

Sterols, such as cholesterol in our bodies or ergosterol in yeast cells, are among the most abundant lipids in eukaryotic cells, yet are synthesized through notoriously long, complex metabolic pathways.

Researchers from UC San Diego and the NIH have used a novel combination of cell biology, in vitro biochemistry and molecular computer simulations to show that in yeast, this pathway shapes the ergosterol to balance its interactions with other lipids. This balancing act allows for the formation of membrane domains—self-assembling structures that are believed to organize proteins in cell membranes.

The work tests and revises a 50-year old textbook model, known as the Bloch hypothesis, for the evolution of sterol in . The results indicate that the complexity of sterol metabolism could have resulted from the need to balance lipid interactions required for membrane organization

"This has been one of my favorite projects," stated Assistant Professor of Chemistry and Biochemistry Itay Budin. "It taught me so much about sterols, their metabolism, and the hoops cells go through to make their lipids dance in just the right way."

The work is in the journal Science Advances.

Simulated motion of three different ergosterol intermediates (yellow) and phospholipids (blue or black based on their ordering of their chains). Credit: Alex Sodt and Itay Budin / UC San Diego

More information: Israel Juarez-Contreras et al, Structural dissection of ergosterol metabolism reveals a pathway optimized for membrane phase separation, Science Advances (2025).

Journal information: Science Advances