A Chemo-Enzymatic Cascade Strategy for the Synthesis of Phosphatidylcholine Incorporated with Structurally Diverse FAHFAs

• Published in: The Journal of Organic Chemistry
• Main Authors: Bogojevic, Oliver, Zhang, Yan, Daugaard Wolff, Christian, Johnsen, Niels Krabbe, Arevång, Carl, Guo, Zheng
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2024
• Subjects: Esters/chemistry; Fatty Acids/chemistry; Humans; Lipase; Molecular Docking Simulation; Phosphatidylcholines; Phospholipids; Antarc*; Antarctica
• Online Access: https://pure.au.dk/portal/en/publications/bcb99828-f00a-4d70-bb85-4279e667af61; https://doi.org/10.1021/acs.joc.3c02131; http://www.scopus.com/inward/record.url?scp=85181578494&partnerID=8YFLogxK

Fatty acid esters of hydroxy fatty acids (FAHFAs), a newly discovered class of human endogenous complex lipids showing great promise for treating diabetes and inflammatory diseases, exist naturally in extremely low concentrations. This work reports a chemo-enzymatic approach for the comprehensive synthesis of phospholipids containing FAHFAs via sequential steps: hydratase-catalyzed hydration of unsaturated fatty acids to generate structurally diverse hydroxy fatty acids (HFAs), followed by the selective esterification of these HFAs with fatty acids mediated by secondary alcohol-specific Candida antarctica lipase A (CALA), resulting in the formation of a series of diverse FAHFA analogs. The final synthesis is completed through carbodiimide-based coupling of FAHFAs with glycerophosphatidylcholine. Optimal reaction conditions are identified for each step, and the substrate affinity of CALA, responsible for the catalytic mechanisms during FAHFA production, is evaluated through molecular docking. Compared to multistep lab-tedious chemical synthesis, this route, relying on natural building blocks and natural biocatalysts, is significantly facile, scalable, and highly selective, affording high yields (74-98 mol %) in each step for the construction of higher FAHFA-PC series (10/12/13-FAHFAs). The developed strategy aims to increase the availability of naturally occurring FAHFA species and provide the tools for the construction of versatile and novel analogs of FAHFA conjugates.