Specialized pro-resolving mediators: Biosynthetic pathways, biocatalytic synthesis, and applications

Specialized pro-resolving mediators (SPMs), a class of di- and trihydroxy fatty acids derived from C20- and C22-polyunsaturated fatty acids, are endogenously produced by human M2 macrophages, polymorphonuclear leukocytes, and other immune and structural cells. They play crucial roles in the resolution of inflammation and infection. Owing to their potent bioactivities, SPMs have attracted considerable interest for applications in food, cosmetics, and clinical therapeutics. Therefore, achieving high concentrations of these mediators is essential. This review provides a comprehensive overview of the nomenclature, classification, biological functions, biosynthetic pathways, and recent advances in the biocatalytic synthesis of SPMs, including lipoxins, resolvins, protectins, and maresins. We examine the biosynthetic pathways: from arachidonic acid to lipoxins; from eicosapentaenoic acid, docosahexaenoic acid, and n-3 docosapentaenoic acid to resolvin E, D, and T series, respectively; and from docosahexaenoic acid to protectins, and maresins. These pathways are catalyzed by fatty acid oxygenases, such as lipoxygenases (LOXs), aspirin-triggered cyclooxygenases, and cytochrome P450 monooxygenases, in combination with hydrolases and peroxidases. Recent advances in microbial biocatalysis, particularly through the use of recombinant cells expressing microbial LOXs, have enabled the efficient synthesis of SPMs. The discovery of microbial double‑oxygenating LOXs has significantly improved production yields, achieving gram-per-liter scale. To further enhance the biocatalytic synthesis, this review discusses enzyme discovery, protein engineering, and biocatalysis optimization strategies aimed at enhancing SPM production. Notably, computational and artificial intelligence-driven approaches are emerging as powerful tools for the discovery and engineering of high-efficiency LOXs, providing a promising route to improve the biocatalytic synthesis of SPMs.