Abstract
Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1–4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1–4.
Highlights
During the resolution of acute inflammation, a novel group of host-protective chemical mediators biosynthesized from the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed specialized pro-resolving mediators (SPMs)[1] and their bioactive peptide-conjugates,[2] are resolution mediators and control tissue regeneration and promote the return to homeostasis.[3,4]
We demonstrate that 13R-HDPA is converted by human neutrophils to all four RvTs, thereby confirming the role of 13R-HDPA as a key biosynthetic intermediate in RvT formation
The RvT family of mediators demonstrated potent protective actions increasing mice survival during Escherichia coli (E. coli) infections, and regulate human and mouse phagocyte responses that result in increased bacterial phagocytosis and regulation of inflammasome components.[8]
Summary
To establish evidence of the existence of 13R-HDPA (5) as a pivotal intermediate and its role in the biosynthesis of the novel 13-series resolvins (RvT 1−4), stereochemically pure 5 was obtained by total synthesis. Isomer of 13-HDPA that was found to be the minor product in both incubations forming ∼10% of the overall 13-HDPA levels in the HUVEC incubations (Figure 2A) and
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