Biotransformation of polyunsaturated fatty acids to bioactive hepoxilins and trioxilins by microbial enzymes

Abstract

Hepoxilins (HXs) and trioxilins (TrXs) are involved in physiological processes such as inflammation, insulin secretion and pain perception in human. They are metabolites of polyunsaturated fatty acids (PUFAs), including arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, formed by 12-lipoxygenase (LOX) and epoxide hydrolase (EH) expressed by mammalian cells. Here, we identify ten types of HXs and TrXs, produced by the prokaryote Myxococcus xanthus, of which six types are new, namely, HXB ₅, HXD ₃, HXE ₃, TrXB ₅, TrXD ₃ and TrXE ₃. We succeed in the biotransformation of PUFAs into eight types of HXs (>35% conversion) and TrXs (>10% conversion) by expressing M. xanthus 12-LOX or 11-LOX with or without EH in Escherichia coli. We determine 11-hydroxy-eicosatetraenoic acid, HXB ₃, HXB ₄, HXD ₃, TrXB ₃ and TrXD ₃ as potential peroxisome proliferator-activated receptor-γ partial agonists. These findings may facilitate physiological studies and drug development based on lipid mediators.

Abstract

Hepoxilins (HXs) and trioxilins (TrXs) are lipid metabolites with roles in inflammation and insulin secretion. Here, the authors discover a prokaryotic source of HXs and TrXs, identify the biosynthetic enzymes and heterologously express HXs and TrXs in E. coli.