Medium- and short-chain fatty acids (C8-C14) are widely used in industries including food, pharmaceuticals, lubricants, and surfactants, and they are currently mainly extracted from coconut and palm oils. Developing sustainable microbial alternatives, especially for producing fatty acids with high purity and precise chain-length control, is a major goal of synthetic biology and metabolic engineering.

In a study published in Nature Chemical Biology, Prof. ZHOU Yongjin's team from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences and Prof. Martin Grininger's team from Goethe University Frankfurt developed a modular and programmable fatty acid synthesis platform which enables high specificity production of medium-chain fatty acids in yeast.

Prof. Grininger's team engineered a metazoan fatty acid synthase (mFAS) through targeted mutations, which can modulate the activity of its ketosynthase (KS) and thioesterase (TesA) domains to precisely control the fatty acid chain length.

Then, Prof. ZHOU's team constructed an efficient yeast cell factory using the industrial yeast Ogataea polymorpha. The optimized mFAS/TesA system was integrated and co-expressed alongside engineered fatty acid metabolism. These modifications blocked the complete degradation of long-chain fatty acids and redirected metabolic flux toward medium-chain products.

The engineered strain XMCFA69, an engineered Ogataea polymorpha strain developed in this study, achieved a medium-chain fatty acid titer of 708.6 mg/L, with lauric acid (C12) accounting for 48% of the total products, which was comparable to its abundance in coconut and palm kernel oils.

"This study develops a programmable, chain-length-controllable platform through synergistic enzyme and metabolic engineering. It demonstrates the potential of synthetic biology for sustainable chemical manufacturing, and offers a viable alternative to plant-based fatty acid extraction," said Prof. ZHOU.

Engineering metazoan fatty acid synthase for chain-length control in yeast. (Image by ZHAI Xiaoxin)