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

Nat Commun. 2018 Jan 9;9(1):128. doi: 10.1038/s41467-017-02543-8.

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, HXB5, HXD3, HXE3, TrXB5, TrXD3 and TrXE3. 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, HXB3, HXB4, HXD3, TrXB3 and TrXD3 as potential peroxisome proliferator-activated receptor-γ partial agonists. These findings may facilitate physiological studies and drug development based on lipid mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives*
  • 8,11,14-Eicosatrienoic Acid / chemistry
  • 8,11,14-Eicosatrienoic Acid / metabolism
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate Lipoxygenases / genetics
  • Arachidonate Lipoxygenases / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biotransformation
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism
  • Fatty Acids, Unsaturated / chemistry
  • Fatty Acids, Unsaturated / metabolism*
  • Metabolic Networks and Pathways / genetics
  • Molecular Structure
  • Myxococcus xanthus / enzymology*
  • Myxococcus xanthus / genetics

Substances

  • Bacterial Proteins
  • Fatty Acids, Unsaturated
  • 8,11,12-trihydroxy-5,9,14-eicosatrienoic acid
  • 8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid
  • 11-lipoxygenase
  • Arachidonate Lipoxygenases
  • Arachidonate 12-Lipoxygenase
  • Epoxide Hydrolases
  • 8,11,14-Eicosatrienoic Acid