Eoxins are a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses) that are produced in human eosinophils (a class of white blood cells) and mast cells through the metabolism of arachidonic acid (an omega-6 (ω-6) fatty acid) by the arachidonate 15-lipoxygenase-1 enzyme.[1][2] The eoxins represent 14,15-leukotriene analogs and are synthesized in a similar manner to the standard leukotrines.[3][2]

History and name

The eoxins are 14,15-analogs of LTA4, LTB4, LTC4, LTD4, and LTE4. Because the leukotrienes and 14,15-leukotrienes have very similar names, the 14,15-leukotrienes were renamed "eoxins" to avoid the confusion that might arise from referring to both group as "leukotrienes".[2][4] The eoxins derive their name from eosinophils, the cell type where they were originally discovered in abundance.[2][4]

Types

EXC4, EXD4, and EXE4

Cover eoxin C4, eoxin D4, and eoxin E4 here.

Biochemistry

Human biosynthesis

Pathway textbook review[5]


Pathway sequence:[3][6]

  1. Arachidonic acid → 15-HPETE via 15-LOX-1 (Pubchem 15-HPETE entry)
  2. 15-HPETE → EXA4 via 15-LOX-1
    (reactome agrees with the 1st reaction above, but indicates that LTA4 → EXA4 via 15-LOX-1 is the only route of human EXA4 synthesis)
  3. EXA4 → EXC4 via LTC4 synthase aka "glutathione S-transferase II" (per reactome + other sources)
  4. EXC4 → EXD4 via unidentified gamma-glutamyltransferase class enzyme (reactome)
  5. EXD4 → EXE4 via unidentified dipeptidase class enzyme (reactome)

EXB4 does not appear to be endogenously synthesized in humans.

Most of Reactome's human arachidonic acid metabolism pathways is below. 

Arachidonic acid metabolism
Hydrolysis of phosphatidylcholine
Arachidonate diffuses across the ER membrane
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
PTGS2 dimer binds celecoxib
Aspirin acetylates PTGS1
Aspirin acetylates PTGS2
Arachidonic acid is oxidised to PGG2 by PTGS1
Arachidonic acid is oxidised to PGG2 by PTGS2
PGG2 is reduced to PGH2 by PTGS1
PGG2 is reduced to PGH2 by PTGS2
PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol
PGH2 is reduced to PGF2a by AKR1C3
PGH2 is reduced to PGF2a by FAM213B
PGH2 is isomerised to PGE2 by PTGES
Prostaglandin E synthase isomerizes PGH2 to PGE2
PGE2 is converted to PGF2a by CBR1
PGE2 is dehydrated to PGA2
PGA2 is isomerised to PGC2
PGC2 is isomerised to PGB2
PGA2 is dehydrated to 15d-PGA2
PGH2 is isomerised to PGD2 by PTGDS
PGH2 is isomerised to PGD2 by HPGDS
PGD2 is dehydrated to PGJ2
PGJ2 is isomerised to delta12-PGJ2
Delta12-PGJ2 is dehydrated to 15d-PGJ2
PGD2 is dehydrated to 15d-PGD2
PGD2 is reduced to 11-epi-PGF2a by AKRIC3
PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD
15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1
PTGIS, CYP8A1 isomerise PGH2 to PGI2
PGI2 is hydrolysed to 6k-PGF1a
TBXAS1 isomerises PGH2 to TXA2
TXA2 is hydrolysed to TXB2 
TXB2 is converted to 11dh-TXB2 by TXDH
PGH2 is degraded to 12S-HHT and MDA by TBXAS1
Synthesis of Leukotrienes (LT) and Eoxins (EX)
ALOX5 is phosphorylated by MAPKAP2
Arachidonic acid is oxidised to 5S-HpETE by ALOX5
5S-HpETE is dehydrated to LTA4 by ALOX5
LTA4 is hydolysed to LTB4 by LTA4H
LTB4 is oxidised to 12-oxoLTB4 by PTGR1
CYP4F2, 4F3 20-hydroxylate LTB4
20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3
20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3
20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH
20cooh-LTB4 is converted to 18cooh-LTB4
LTA4 is converted to LTC4 by LTC4S
LTC4 is exported from the cytosol by ABCC1
LTC4 is converted to LTD4 by GGT1/5
LTD4 is converted to LTE4 by DPEP1/2
LTA4 is hydrolysed to 6t-/6t,12epi-LTB4
LTA4 is converted to EXA4 by ALOX15
EXA4 is converted to EXC4 by LTC4S
EXC4 is converted to EXD4 by GGT
EXD4 is converted to EXE4 by DPEP
Synthesis of 5-eicosatetraenoic acids
Arachidonic acid is oxidised to 5S-HpETE by ALOX5
5S-HpETE is reduced to 5S-HETE by GPX1/2/4
5S-HETE is oxidised to 5-oxoETE by 5-HEDH
Synthesis of 15-eicosatetraenoic acid derivatives
Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B
15S-HpETE is reduced to 15S-HETE by GPX1/2/4
15S-HETE is oxidised to 15-oxoETE by 15-HEDH
Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2
Synthesis of 12-eicosatetraenoic acid derivatives
Arachidonic acid is oxidised to 12R-HpETE by ALOX12B
12R-HpETE is reduced to 12R-HETE by GPX1/2/4
Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15
12S-HpETE is reduced to 12S-HETE by GPX1/2/4
Arachidonic acid is converted to 12-oxoETE by ALOX12
Synthesis of Lipoxins (LX)
LTA4 is converted to LXA4/B4 by ALOX12
15S-HpETE is oxidised to LXA4/B4 by ALOX5 [Homo sapiens]
15R-HETE is converted to 15epi-LXA4/B4 by ALOX5
LXA4 is oxidised to 15k-LXA4 by HPGD
15k-LXA4 is reduced to dhk-LXA4 by PTGR1
Synthesis of Hepoxilins (HX) and Trioxilins (TrX)
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)
Arachidonic acid is epoxidated to 5,6-EET by CYP(4)
Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5)
EET(1) is hydrolysed to DHET(1) by EPHX2

Function

[6]

Role in allergic airway inflammation

[3][7][6]

Role in cancer

[1]

See also

.

Reviews

[8]

[1]

[3]

Context note: 15-LOX-1 metabolizes (ω-6 fatty acid) arachidonic acid into eoxins, but also metabolizes the (ω-3 fatty acid) docosahexaenoic acid (DHA) into neuroprotectin D1.[9] (cited by review)

Lipid database entry on Eoxins[6]

Primary literature

[2]

[10]

[11]

[12]

[13]

[7]

References

  1. ^ a b c Greene ER, Huang S, Serhan CN, Panigrahy D (2011). "Regulation of inflammation in cancer by eicosanoids". Prostaglandins Other Lipid Mediat. 96 (1–4): 27–36. doi:10.1016/j.prostaglandins.2011.08.004. PMC 4051344. PMID 21864702. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenase (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (2008). "Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells". Proc. Natl. Acad. Sci. U.S.A. 105 (2): 680–685. doi:10.1073/pnas.0710127105. PMC 2206596. PMID 18184802. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b c d Claesson HE (2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma". Prostaglandins Other Lipid Mediat. 89 (3–4): 120–5. doi:10.1016/j.prostaglandins.2008.12.003. PMID 19130894. ((cite journal)): Unknown parameter |month= ignored (help)
  4. ^ a b "European patent specification: METHODS FOR IDENTIFYING MODULATORS OF EOXIN FORMATION" (PDF). www.lens.org. 18 August 2010. p. 26. Retrieved 5 January 2015. Since eosinophils are a rich source of these novel metabolites, we suggest the name eoxin instead of 14,15-leukotriene to avoid confusion with compounds produced via the 5-LO pathway. Thus, the names 14,1 5-leukotriene A4, C4, D4 and E4 are replaced with eoxin (Eox) A4, EoxC4, EoxD4 and EoxE4, respectively (fig. 33). Eoxins have never been reported to be produced from arachidonic acid in human cells. Human basophils, however, has earlier been found to convert exogenous 14,15-leukotriene A4 to 14,15-leukotriene C4 (33)14(R),15(s)-DHETE
  5. ^ Cite error: The named reference Eoxin subtypes EXA4–EXE4 was invoked but never defined (see the help page).
  6. ^ a b c d "3. Eoxins". The AOCS Lipid Library. 26 May 2014. Retrieved 5 January 2015. Recently, novel eicosanoids related to the cysteinyl-leukotrienes were characterized as products of the 12/15-lipoxygenase (15-LOX-1) of human eosinophils and mast cells. The primary product of the lipoxygenase, 15-HPETE is believed to react with the enzyme further to produce the 14,15-epoxide, designated eoxin A4, and then by analogy with leukotriene biosynthesis this in turn reacts with glutathione to produce eoxin C4, and thence eoxin D4 (linked to Cys-Gly) and eoxin E4 (linked to Cys only). Like the cysteinyl-leukotrienes, the eoxins are potent pro-inflammatory agents. ... Eoxins have been implicated in inflammation of the airways in asthma patients, and in those with Hodgkin lymphoma, a malignant disorder with many characteristics of an inflammatory illness.
  7. ^ a b Matoso A, Allen D, Herzlinger M, Ferreira J, Chen S, Lu S, Fabre V, Monahan R, Yang D, Noble L, Mangray S, Resnick MB (2014). "Correlation of ALOX15 expression with eosinophilic or reflux esophagitis in a cohort of pediatric patients with esophageal eosinophilia". Hum. Pathol. 45 (6): 1205–12. doi:10.1016/j.humpath.2014.01.021. PMID 24742828. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Kuhn H, Banthiya S, van Leyen K (October 2014). "Mammalian lipoxygenases and their biological relevance". Biochim. Biophys. Acta. doi:10.1016/j.bbalip.2014.10.002. PMID 25316652.((cite journal)): CS1 maint: multiple names: authors list (link)
  9. ^ Bazan NG (2009). "Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease". J. Lipid Res. 50 Suppl: S400–5. doi:10.1194/jlr.R800068-JLR200. PMC 2674685. PMID 19018037. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  10. ^ Sachs-Olsen C, Sanak M, Lang AM, Gielicz A, Mowinckel P, Lødrup Carlsen KC, Carlsen KH, Szczeklik A (2010). "Eoxins: a new inflammatory pathway in childhood asthma". J. Allergy Clin. Immunol. 126 (4): 859–867.e9. doi:10.1016/j.jaci.2010.07.015. PMID 20920774. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Brunnström Å, Backman L, Tryselius Y, Claesson HE (2012). "Biosynthesis of eoxin C4 by porcine leukocytes". Prostaglandins Leukot. Essent. Fatty Acids. 87 (4–5): 159–163. doi:10.1016/j.plefa.2012.07.003. PMID 22921794.((cite journal)): CS1 maint: multiple names: authors list (link)
  12. ^ James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE (2013). "The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma". Int. Arch. Allergy Immunol. 162 (2): 135–142. doi:10.1159/000351422. PMID 23921438.((cite journal)): CS1 maint: multiple names: authors list (link)
  13. ^ Forsell PK, Brunnström A, Johannesson M, Claesson HE (2012). "Metabolism of anandamide into eoxamides by 15-lipoxygenase-1 and glutathione transferases". Lipids. 47 (8): 781–791. doi:10.1007/s11745-012-3684-z. PMID 22684912. ((cite journal)): Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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