Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases. Recently, it was identified that the bioactivities of omega-3 are related to lipid mediators, called pro-resolving lipid mediators (SPMs), converted from PUFAs, so they have attracted much attention as potential pharmaceutical targets. Here, we aimed to build an efficient production system composed of enzymatic and chemical catalysis that converts docosahexaenoic acid (DHA) into lipid mediators. The cyanobacterial lipoxygenase, named Osc-LOX, was identified and characterized, and the binding poses of enzyme and substrates were predicted by ligand docking simulation. DHA was converted into three lipid mediators, a 17S-hydroxy-DHA, a 7S,17S-dihydroxy-DHA (RvD5), and a 7S,15R-dihydroxy-16S,17S-epoxy-DPA (new type), by an enzymatic reaction and deoxygenation. Also, two lipid mediators, 7S,15R,16S,17S-tetrahydroxy-DPA (new type) and 7S,16R,17S-trihydroxy-DHA (RvD2), were generated from 7S,15R-dihydroxy-16S,17S-epoxy-DPA by a chemical reaction. Our study suggests that discovering new enzymes that have not been functionally characterized would be a powerful strategy for producing various lipid mediators. Also, this combination catalysis approach including biological and chemical reactions could be an effective production system for the manufacturing lipid mediators.
Highlights
Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases
The metal-binding amino acids in all LOXs were perfectly conserved as the motif, HHHN(H/S)I; Osc-LOX incorporates a methionine in the last position instead of isoleucine
The final product stayed on the OD-H column for 82 min and its peak did not overlap those for any of the standards, as expected (Supplementary Fig. S6). These results indicate that the first and second products of the catalysis of docosahexaenoic acid (DHA) by Osc-LOX matched the stereo-configuration as well as the regio-configuration of 17S-HDHA and 7S,17S-diHDHA (RvD5), further supporting the possibility that the final product may be a new type of lipid mediator
Summary
Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases. Our study suggests that discovering new enzymes that have not been functionally characterized would be a powerful strategy for producing various lipid mediators This combination catalysis approach including biological and chemical reactions could be an effective production system for the manufacturing lipid mediators. Lipid mediators, such as resolvins and protectins, as bioactive signaling molecules are converted from EPA and DHA via lipoxygenase enzymatic reaction at inflamed s ites[1]. Lipid mediators behind the beneficial effects of omega-3 fatty acids have attracted much attention as important pharmaceutical targets for the protection and treatment for chronic inflammatory diseases. Two new types of lipid mediators were generated by combinatorial catalysis consisting of an enzyme-based biological catalyst with a simple chemical catalyst
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