Poxytrin

Poxytrins are metabolites of docosahexaenoic acid (DHA), arachidonic acid (AA), and α-linolenic acid (ALA). Poxytrins derived from AA are termed linotrins.{{cite journal | vauthors = Lagarde M, Véricel E, Liu M, Chen P, Guichardant M | title = Structure-function relationships of non-cyclic dioxygenase products from polyunsaturated fatty acids: poxytrins as a class of bioactive derivatives | journal = Biochimie | volume = 107 Pt A | pages = 91–4 | year = 2014 | pmid = 25223888 | doi = 10.1016/j.biochi.2014.09.008 | s2cid = 31338779 | url = https://www.hal.inserm.fr/inserm-01072459/file/Lagarde_et_al_biochimie_revue.pdf}}

Protectin DX (PDX) is perhaps the most prominent poxytrin. It is not to be confused with its isomer protectin D1 (PD1). PD1 is structurally identical to PDX except that its three conjugated double bonds 11E,13E,15Z have the E,E,Z configuration. PDX and PD1 both possess potent specialized pro-resolving mediator (SPM) anti-inflammatory activity, but only PDX inhibits human platelet aggregation responses.{{cite journal | vauthors = Balas L, Guichardant M, Durand T, Lagarde M | title = Confusion between protectin D1 (PD1) and its isomer protectin DX (PDX). An overview on the dihydroxy-docosatrienes described to date | journal = Biochimie | volume = 99 | pages = 1–7 | year = 2014 | pmid = 24262603 | doi = 10.1016/j.biochi.2013.11.006 }} PDX's anti-platelet activity is shared with various other dihydroxy-E,Z,E-PUFAs, but not with dihydroxy-PUFAs that have an E,E,E or E,E,Z configuration.{{cite journal | vauthors = Chen P, Véricel E, Lagarde M, Guichardant M | title = Poxytrins, a class of oxygenated products from polyunsaturated fatty acids, potently inhibit blood platelet aggregation | journal = FASEB Journal | volume = 25 | issue = 1 | pages = 382–8 | year = 2011 | pmid = 20833872 | doi = 10.1096/fj.10-161836 | doi-access = free | s2cid = 21164301 }}

Cells make PDX by metabolizing DHA by double oxygenation with a 15-lipoxygenase to form the 10R,17S-hydroxperoxy intermediate which is reduced to its 10R,17S-hydroxyl product, PDX, probably by cytosolic glutathione peroxidase 1 (GPX1). Serial metabolism by two different lipoxygenases or by a lipoxygenase and a cytochrome P45 on a 1Z,4Z,7Z-PUFA may also make a 1,7-dihydroxy 2E,4Z,6E product.

• 10R,17S-diHDHA is the 10R diastereomer of PDX, with the 10R hydroxyl residue being formed by aspirin-treated COX-2 or a cytochrome P450.
• 8S,15S-diHETE has been observed in guinea pig tissues, probably made through double oxygenation of AA by a 15-lipoxygenase (probably ALOX15) or serial metabolism by two enzymes.{{cite journal | vauthors = Sehmi R, Cromwell O, Taylor GW, Kay AB | title = Identification of guinea pig eosinophil chemotactic factor of anaphylaxis as leukotriene B4 and 8(S),15(S)-dihydroxy-5,9,11,13(Z,E,Z,E)-eicosatetraenoic acid | journal = Journal of Immunology | volume = 147 | issue = 7 | pages = 2276–83 | year = 1991 | doi = 10.4049/jimmunol.147.7.2276 | pmid = 1655889 | s2cid = 19598067 | doi-access = free }}
• 10S,17S-diHDHA is the 13Z cis–trans isomer of 10-epi-protectin D (which has a 13E double bond instead). 10S,17S-diHDHA is formed in vitro by stimulated human leukocytes and possesses SPM anti-inflammatory activity.{{cite journal | vauthors = Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA | title = Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes | journal = Journal of Immunology | volume = 176 | issue = 3 | pages = 1848–59 | year = 2006 | pmid = 16424216 | doi = 10.4049/jimmunol.176.3.1848| doi-access = free }}
• 7-epi-MaR1 is a maresin isomer1, and likewise possesses SPM activity.

Linotrin-1 and linotrin-2 are among the four isomeric metabolites produced by incubating ALA with ALOX15B.{{cite journal | vauthors = Liu M, Chen P, Véricel E, Lelli M, Béguin L, Lagarde M, Guichardant M | title = Characterization and biological effects of di-hydroxylated compounds deriving from the lipoxygenation of ALA | journal = Journal of Lipid Research | volume = 54 | issue = 8 | pages = 2083–94 | year = 2013 | pmid = 23740966 | pmc = 3708359 | doi = 10.1194/jlr.M035139 |doi-access=free | url = http://www.hal.inserm.fr/inserm-00832286/document}} The extent to which the linotrins form in cells or in vitro is not clear.

Stimulating agents such as collagen depend on platelets to make and release [[Thromboxane A2|

thromboxane A₂]] (TXA₂) to mediate and/or enhance their aggregating activity. 10R,17S-diHDHA, and PDX to a slightly lesser degree, inhibit the human platelet aggregation response to collagen at ≥ 100–200 nanomolar concentrations. This appears to reflect the ability of poxytrins to inhibit the activities of COX-1 and COX-2, thereby blocking the production of TXA₂ and thus interfering with the activation of the thromboxane receptor by TXA₂. The linotrins appear to use a similar mechanism, and to have similar or slightly lower potencies. However, the linotrins are 20- to 100-fold stronger in inhibiting human platelet aggregation compared to 5-HETE and 12-HETE, two mono-hydroxyl-containing eicosanoids that contain an E,Z conjugated double bond configuration.{{cite journal | vauthors = Croset M, Lagarde M | title = Stereospecific inhibition of PGH2-induced platelet aggregation by lipoxygenase products of icosaenoic acids | journal = Biochemical and Biophysical Research Communications | volume = 112 | issue = 3 | pages = 878–83 | year = 1983 | pmid = 6405751 | doi = 10.1016/0006-291x(83)91699-6}} Other biologically-active poxytrins have yet to be tested for, but are projected to possess anti-platelet activity.

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Category:Cell biology

Category:Cell communication

Category:Cell signaling

Category:Immunology

Category:Fatty acids