Wang_2024_N.Biotechnol__

Fatty acids (FAs) and their derivatives are versatile chemicals widely used in various industries. Synthetic biology, using microbial cell factories, emerges as a promising alternative technology for FA production. To enhance the production capacity of these microbial chassis, additional engineering strategies are imperative. Based on the comparison of the morphological changes of lipid droplets (LDs) between oleaginous and non-oleaginous yeasts, we developed a new engineering strategy to increase the accumulation of FAs in Saccharomyces cerevisiae through manipulation of regulation factor and lipases related to LD. The increased biogenesis of LDs, achieved by overexpressing the interorganelle tethering protein Mdm1, coupled with the accelerated degradation of LDs through upregulated lipases, resulted in a 10.70-fold increase in total FAs production. Co-overexpression of Mdm1 and selected lipases significantly improved the biosynthesis of FAs and linoleic acid in the engineered S. cerevisiae. The efficient LD-based metabolic engineering strategy presented in this study holds the potential to advance the high-level production of FAs and their derivatives in microbial cell factories.