Synthesis of the 16<i>S</i>,17<i>S</i>-Epoxyprotectin Intermediate in the Biosynthesis of Protectins by Human Macrophages

Aursnes, Marius; Tungen, Jørn Eivind; Colas, Romain A.; Vlasakov, Iliyan; Dalli, Jesmond; Serhan, Charles N.; Hansen, Trond Vidar

doi:10.1021/acs.jnatprod.5b00574

Cited by 41 publications

(63 citation statements)

References 39 publications

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“…In addition, our results demonstrate that 16S,17S-epoxyprotectin is an intermediate for PCTR1 biosynthesis, because it is converted to this potent mediator by human macrophages and matches the endogenous alcohol trapping product of this key intermediate. 13 Importantly, we show that the novel peptide-conjugate PCTR1 has unique biological functions distinctly from either PD1 or D-series resolvins at nanomolar and picomolar concentrations. Our results demonstrate that PCTR1 promotes nonphlogistic human monocyte and macrophage recruitment and enhances host-directed antimicrobial responses in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 79%

“…26,27 PCTR1 shares substrate intermediates with PD1 and D-series resolvins. 7,13 Distinctly, PCTR1 at 1 nmol/L did not affect IL-10 levels (data not shown), a known function of PD1 and RvD1. 14,28 In addition, PCTR1 has characteristic tissue regenerative roles and enhances human macrophage phagocytosis and efferocytosis.…”

Section: Discussionmentioning

confidence: 80%

“…The products were then suspended in methanol, and the biological PCTR1 was isolated with an Agilent 1260 Infinity reverse phase UVehigh-performance liquid chromatography system with a Poroshell 120 EC-C18 column (100 mm Â 4.6 mm Â 2.7 mm; Agilent Technologies) and a methanol/water/acetic acid gradient as described in the previous section. For the organic synthesis of PCTR1, the synthetic epoxide intermediate 16S,17S-epoxy-protectin methyl ester 13 was added to 10 equivalents of glutathione suspended in a 3:1 solution of MeOH/piperidine. The reaction was stirred vigorously under argon for 4 hours.…”

Section: Synthetic Pctr1 Preparationmentioning

confidence: 99%

“…6 PCTR1 was synthesized by opening the synthetic 16S,17S-epoxy-protectin methyl ester 13 (Figure 7, C and D). In addition, coinjections of the synthetic PCTR1 free acid and biologically generated PCTR1 gave a single peak with R T at 10.0 minutes (Figure 7, E and F).…”

Section: Synthesis Characterization and Matching Of Synthetic Pctr1mentioning

confidence: 99%

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The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

Ramon

Dalli

Sanger

et al. 2016

The American Journal of Pathology

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Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative actions that belong to the protectin family and are coined protectin conjugates in tissue regeneration (PCTR). Herein, with the use of microbial-induced peritonitis in mice and liquid chromatography-tandem mass spectrometryebased lipid mediator metabololipidomics, we found that PCTR1 is temporally regulated during self-resolving infection. When administered at peak of inflammation, PCTR1 enhanced macrophage recruitment and phagocytosis of Escherichia coli, decreased polymorphonuclear leukocyte infiltration, and counter-regulated inflammation-initiating lipid mediators, including prostaglandins. In addition, biologically produced PCTR1 promoted human monocyte and macrophage migration in a dose-dependent manner (0.001 to 10.0 nmol/L). We prepared PCTR1 via organic synthesis and confirmed that synthetic PCTR1 increased macrophage and monocyte migration, enhanced macrophage efferocytosis, and accelerated tissue regeneration in planaria. With human macrophage subsets, PCTR1 levels were significantly higher in M2 macrophages than in M1 phenotype, along with members of the resolvin conjugates in tissue regeneration and maresin conjugate families. In contrast, M1 macrophages gave higher levels of cysteinyl leukotrienes. Together, these results demonstrate that PCTR1 is a potent monocyte/macrophage agonist, regulating key anti-inflammatory and pro-resolving processes during bacterial infection. (Am J Pathol 2016, 186: 962e973; http://dx

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 80%

Section: Synthetic Pctr1 Preparationmentioning

confidence: 99%

Section: Synthesis Characterization and Matching Of Synthetic Pctr1mentioning

confidence: 99%

See 2 more Smart Citations

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

Ramon

Dalli

Sanger

et al. 2016

The American Journal of Pathology

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115

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“…This idea may explain why the presence of an OH moiety near the carboxylate group as in (±)4OH DHA is better tolerated. Physiologically, DHA is converted to other signaling molecules such as maresin 1 (22), protectin D1 and DX (23), and 17-keto DHA (24) with multiple OH groups. Our findings here predict that these metabolites are without any effect and this prediction is indeed borne out (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 99%

Atomic determinants of BK channel activation by polyunsaturated fatty acids

Tian

Aursnes

Hansen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca 2+ -and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery. -4,7,10,13,16,19-hexaenoic acid], found abundantly in oily fish, are believed to have many health-promoting effects (1). For example, select ω-3 PUFAs may decrease cardiovascular disease risk (2). Furthermore, human studies suggest that ω-3 PUFAs may lower blood pressure in some individuals (3). Thus, PUFAs such as DHA are natural nutraceuticals with great potential as lead compounds for rational drug design and discovery. To be successful, such an effort requires clear mechanistic understanding of the interactions between PUFAs and their effectors (4); however, the molecular targets of PUFAs and the mechanisms of action are only beginning to be revealed.One of the high-affinity targets of PUFAs is the large-conductance Ca 2+ -and voltage-gated K + (Slo1 BK) channel (5), whose activation in vascular smooth muscle cells facilitates vessel relaxation (6). Vascular Slo1 BK channels made of four pore-forming Slo1 and auxiliary β1 subunits (Slo1 + β1) are potently and reversibly activated by DHA with a nanomolar level of EC 50 , and this effect contributes to the hypotensive action of DHA in wild-type mice but not in mice with the gene encoding the channel (KCNMA1) disrupted (5).The function of the Slo1 BK channel can be electrophysiologically monitored with high precision to produce quantitative results amenable to mechanistic interpretations (7,8). Such in vitro studies show that DHA biases the ion conduction gate of the channel toward the open conformation without any need for activation of the channel's Ca 2+ sensors in the intracellular domain or transmembrane voltage sensor domains (VSDs) (5). Structurally, the action of DHA depends on a Tyr residue [Y318 in human Slo1 (hSlo1)] near the intracellular end of the ion conduction pathway; the mutation Y318S abolishes the activating effect of DHA (9).The exact role of Y318 in mediating the effect of DHA, however, is not clear. Some clues may be gained from interactions of other proteins with PUFAs. Extracellular DHA regulates voltagegated K + channels by interacting with ...

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Stereochemistry and functions of the new cysteinyl‐resolvin, 4S,5R‐RCTR1, in efferocytosis and erythrophagocytosis of human senescent erythrocytes

et al. 2023

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Specialized pro‐resolving lipid mediators play key functions in the resolution of the acute inflammatory response. Herein, we elucidate the stereochemical structure of the new 4S,5R‐RCTR1, a cysteinyl‐resolvin, recently uncovered in human leukocytes incubated with a 4S,5S‐epoxy‐resolvin intermediate, using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and ultra‐violet (UV) spectrophotometry. With this approach, the physical properties of the new mediator prepared by total organic synthesis were matched to enzymatically produced biogenic material. In addition, we confirmed the potent biological actions of 4S,5R‐RCTR1 with human M2‐like macrophage phagocytosis of live bacteria, efferocytosis of apoptotic neutrophils, and erythrophagocytosis of senescent human red blood cells in a concentration‐dependent manner from 0.1 to 10 nM. Taken together, these results establish the complete stereochemistry of 4S,5R‐RCTR1 as 5R‐glutathionyl‐4S,17S‐dihydroxy‐6E,8E,10Z,13Z,15E,19Z‐docosahexaenoic acid and give evidence of its novel bioactivities in human phagocyte responses. Moreover, they confirm and extend the stereoselective functions of the 4S,5R‐RCTR1 with isolated human phagocytes of interest in the resolution of inflammation.

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Synthesis of the 16S,17S-Epoxyprotectin Intermediate in the Biosynthesis of Protectins by Human Macrophages

Cited by 41 publications

References 39 publications

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation

Atomic determinants of BK channel activation by polyunsaturated fatty acids

Stereochemistry and functions of the new cysteinyl‐resolvin, 4S,5R‐RCTR1, in efferocytosis and erythrophagocytosis of human senescent erythrocytes

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