Biogenic Synthesis, Purification, and Chemical Characterization of Anti-inflammatory Resolvins Derived from Docosapentaenoic Acid (DPAn-6)

Abstract

Chem. 278, 14677-14687). Our objective was to determine whether similar derivatives are enzymatically synthesized from other C-22 fatty acids and whether these molecules possess inflammation resolution properties. The reaction of DHA, DPAn-3, and DPAn-6 with 5-, 12-, and 15-lipoxygenases produced oxylipins, which were identified and characterized by liquid chromatography coupled with tandem mass-spectrometry. DPAn-6 and DPAn-3 proved to be good substrates for 15-lipoxygenase. 15-Lipoxygenase proved to be the most efficient enzyme of the three tested for conversion of long chain polyunsaturated fatty acids to corresponding oxylipins. Since DPAn-6 is a major component of Martek DHA-S TM oil, we focused our attention on reaction products obtained from the DPAn-6 and 15-lipoxygenase reaction. (17S)-hydroxy-DPAn-6 and (10,17S)-dihydroxy-DPAn-6 were the main products of this reaction. These compounds were purified by preparatory high performance liquid chromatography techniques and further characterized by NMR, UV spectrophotometry, and tandem mass spectrometry. We tested both compounds in two animal models of acute inflammation and demonstrated that both compounds are potent anti-inflammatory agents that are active on local intravenous as well as oral administration. These oxygenated DPAn-6 compounds can thus be categorized as a new class of DPAn-6-derived resolvins.

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

“…In fact, DPA is reported to be a more potent COX-1 inhibitor than EPA (38). DPA-derived, resolvin-like anti-inflammatory molecules have also been recently identified (39).…”

Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation

“…8,72 These results first demonstrated that the type of eicosanoid and/or LM produced locally is both spatial and temporally regulated (Figure 2). This new concept of resolution-phase mediators and their potent actions has been confirmed 24,25,66 and extended, [73][74][75] includ- …”

Gradient Temperature Raman Spectroscopy of Fatty Acids with One to Six Double Bonds Identifies Specific Carbons and Provides Systematic Three Dimensional Structures

“…Our improved lipid spectroscopy and 3D structures likely have bearing on the enzymatic oxidation processes which form specialized pro-resolving mediators. For example, at 0˚C soybean 15-lipoxygenase oxidizes C17 to its hydroperoxy derivative with 100% efficiency for n-6 DPA, 85% for n-3DPA and 50% for DHA [9]. Figure 5 gives a view of these LC-PUFA in the critical area.…”

“…While conventional Raman analysis can be useful, to first order the long-chain polyunsaturated fatty acids (LC-PUFA) appear nearly identical, with the vibrational modes of most moieties degenerate, redundant or very broad [5] [6] [7] [8] [9]. But logically this cannot be the case, because the LC-PUFA are so vastly different biochemically.…”

“…In particular, the emerging field of specialized pro-resolving mediators provides promising and exciting targets for new anti-inflammatory, neuroprotective and anti-infective drugs and natural products [9] [10] [11] [12] [13]. Specialized pro-resolving mediators are highly interesting in that metabolites of not just DHA and EPA, but also n-3DPA and n-6DPA can actively resolve inflammation at very low concentrations, proving new insight into the numerous health benefits epidemiologically associated with diets high in fish and/or total LC-PUFA [14] [15] [16] [17].…”