Biosynthesis of EPA-derived SPMs (Homo sapiens)

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5, 7, 14, 16173, 4, 123, 126, 1393, 122, 1014, 183, 123, 121, 86, 13183, 4, 12141, 814cytosol18(S)-RvE1O2(18S)-hydroperoxyicosapentaenoic acid18(R)-HEPELTA4H 18(S)-RvE2 NADPHNADPHLTA4H:Zn2+EPANADH(5Z,8Z,11Z,14Z,16E,18R)-18-hydroperoxyicosapentaenoic acid LTA4H:Zn2+heme b NADP+18(S)-RvE318(R)-RvE1,E2,E3ALOX15LTA4H O2HPGD dimerH+GSSGPTGS2 H2O(18R)-resolvin E3O218(S)-RvE1 5(S)-Hp-18(R)-HEPECYP(5Z,8Z,11Z,14Z,16E,18R)-18-hydroperoxyicosapentaenoic acidGSHNADP+ALOX518-oxo-RvE1O25S,6S-epoxy-18(R)-HEPE18(R)-RvE2 ALOX5NAD+18(S)-RvE2 (18R)-resolvin E3 18(S)-RvE1,E2,E318(R)-RvE1,E2,E3H2O18(R)-RvE218(S)-HEPEAc-PTGS2 dimer18(S)-RvE1 5-HEDHHPGD 18(R)-RvE1O2O-acetyl-L-serine-PTGS2 18(S)-RvE218(R)-RvE1 O2(18S)-hydroperoxyicosapentaenoic acid 18(S)-HpEPE,18(R)-HpEPE5(S)-Hp-18(S)-HEPEGPX4-2Zn2+ (18R)-resolvin E3 18(S)-RvE1,E2,E3H2OZn2+ H2O5S,6S-epoxy-18(S)-HEPE18(R)-RvE2 18(S)-RvE3 18(S)-RvE3 18(R)-RvE1 1511


Description

Eicosapentaenoic acid (EPA), a major ω-3 polyunsaturated fatty acid (PUFA) found in fish oil is the source of E-series resolvins (RvEs), one of the specialized proresolving mediators (SPMs) that show potent anti-inflammatory and pro-resolving actions (Molfino et al. 2017). The biosynthesis of RvEs occurs mainly during the process of inflammation when endothelial cells interact with leukocytes. EPA, circulating in plasma or released/mobilised from damaged cellular membranes on injury or infection, moves with edema into the tissue sites of acute inflammation where it is converted to exudate RvEs to interact with local immune cells (Kasuga et al. 2008). The initial transformation of EPA by aspirin-acetylated cyclooxygenase 2- and/or cytochrome P450-mediated catalysis can produce stereospecific resolvins (18(R)- or 18(S)-RvEs). Combinations of oxidation, reduction and hydrolysis reactions determine the type of resolvin formed (RvE1, RvE2 or RvE3) (Serhan et al. 2000, 2002, Serhan & Petasis 2011, Maehre et al. 2015). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9018679
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Isobe Y, Arita M, Matsueda S, Iwamoto R, Fujihara T, Nakanishi H, Taguchi R, Masuda K, Sasaki K, Urabe D, Inoue M, Arai H.; ''Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.''; PubMed Europe PMC
  2. Hong S, Porter TF, Lu Y, Oh SF, Pillai PS, Serhan CN.; ''Resolvin E1 metabolome in local inactivation during inflammation-resolution.''; PubMed Europe PMC
  3. Oh SF, Dona M, Fredman G, Krishnamoorthy S, Irimia D, Serhan CN.; ''Resolvin E2 formation and impact in inflammation resolution.''; PubMed Europe PMC
  4. Patel P, Cossette C, Anumolu JR, Erlemann KR, Grant GE, Rokach J, Powell WS.; ''Substrate selectivity of 5-hydroxyeicosanoid dehydrogenase and its inhibition by 5-hydroxy-Delta6-long-chain fatty acids.''; PubMed Europe PMC
  5. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL.; ''Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.''; PubMed Europe PMC
  6. Han X, Fan Z, Yu Y, Liu S, Hao Y, Huo R, Wei J.; ''Expression and characterization of recombinant human phospholipid hydroperoxide glutathione peroxidase.''; PubMed Europe PMC
  7. Serhan CN, Petasis NA.; ''Resolvins and protectins in inflammation resolution.''; PubMed Europe PMC
  8. Isobe Y, Arita M, Iwamoto R, Urabe D, Todoroki H, Masuda K, Inoue M, Arai H.; ''Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3.''; PubMed Europe PMC
  9. McGee J, Fitzpatrick F.; ''Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes.''; PubMed Europe PMC
  10. Arita M, Oh SF, Chonan T, Hong S, Elangovan S, Sun YP, Uddin J, Petasis NA, Serhan CN.; ''Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions.''; PubMed Europe PMC
  11. Lecomte M, Laneuville O, Ji C, DeWitt DL, Smith WL.; ''Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin.''; PubMed Europe PMC
  12. Tjonahen E, Oh SF, Siegelman J, Elangovan S, Percarpio KB, Hong S, Arita M, Serhan CN.; ''Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis.''; PubMed Europe PMC
  13. Yagi K, Komura S, Kojima H, Sun Q, Nagata N, Ohishi N, Nishikimi M.; ''Expression of human phospholipid hydroperoxide glutathione peroxidase gene for protection of host cells from lipid hydroperoxide-mediated injury.''; PubMed Europe PMC
  14. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K.; ''Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.''; PubMed Europe PMC
  15. Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL.; ''Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer.''; PubMed Europe PMC
  16. Maehre HK, Jensen IJ, Elvevoll EO, Eilertsen KE.; ''ω-3 Fatty Acids and Cardiovascular Diseases: Effects, Mechanisms and Dietary Relevance.''; PubMed Europe PMC
  17. Arnold C, Markovic M, Blossey K, Wallukat G, Fischer R, Dechend R, Konkel A, von Schacky C, Luft FC, Muller DN, Rothe M, Schunck WH.; ''Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids.''; PubMed Europe PMC
  18. Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN.; ''Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
102029view16:17, 26 November 2018Marvin M2Ontology Term : 'eicosanoid biosynthetic pathway' added !
102028view16:16, 26 November 2018Marvin M2Reverted to version '16:15, 26 November 2018' by Marvin M2
102027view16:15, 26 November 2018Marvin M2Ontology Term : 'PW:0001239' removed !
102026view16:15, 26 November 2018Marvin M2Ontology Term : 'PW:0000029' removed !
102025view16:14, 26 November 2018Marvin M2Ontology Term : 'unsaturated fatty acid biosynthetic pathway' added !
101693view14:27, 1 November 2018DeSlOntology Term : 'eicosanoid biosynthetic pathway' added !
101692view14:27, 1 November 2018DeSlOntology Term : 'fatty acid biosynthetic pathway' added !
101691view14:26, 1 November 2018DeSlchanged weird symbols
101500view11:37, 1 November 2018ReactomeTeamreactome version 66
101037view21:17, 31 October 2018ReactomeTeamreactome version 65
100728view20:11, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(18R)-resolvin E3 MetaboliteCHEBI:138542 (ChEBI)
(18R)-resolvin E3MetaboliteCHEBI:138542 (ChEBI)
(18S)-hydroperoxyicosapentaenoic acid MetaboliteCHEBI:138387 (ChEBI)
(18S)-hydroperoxyicosapentaenoic acidMetaboliteCHEBI:138387 (ChEBI)
(5Z,8Z,11Z,14Z,16E,18R)-18-hydroperoxyicosapentaenoic acid MetaboliteCHEBI:138565 (ChEBI)
(5Z,8Z,11Z,14Z,16E,18R)-18-hydroperoxyicosapentaenoic acidMetaboliteCHEBI:138565 (ChEBI)
18(R)-HEPEMetaboliteCHEBI:81563 (ChEBI)
18(R)-RvE1 MetaboliteCHEBI:81559 (ChEBI)
18(R)-RvE1,E2,E3ComplexR-ALL-9023979 (Reactome)
18(R)-RvE1,E2,E3ComplexR-ALL-9023981 (Reactome)
18(R)-RvE1MetaboliteCHEBI:81559 (ChEBI)
18(R)-RvE2 MetaboliteCHEBI:81560 (ChEBI)
18(R)-RvE2MetaboliteCHEBI:81560 (ChEBI)
18(S)-HEPEMetaboliteCHEBI:132801 (ChEBI)
18(S)-HpEPE, 18(R)-HpEPEComplexR-ALL-9022921 (Reactome)
18(S)-RvE1 MetaboliteCHEBI:137038 (ChEBI)
18(S)-RvE1,E2,E3ComplexR-ALL-9023985 (Reactome)
18(S)-RvE1,E2,E3ComplexR-ALL-9029501 (Reactome)
18(S)-RvE1MetaboliteCHEBI:137038 (ChEBI)
18(S)-RvE2 MetaboliteCHEBI:137034 (ChEBI)
18(S)-RvE2MetaboliteCHEBI:137034 (ChEBI)
18(S)-RvE3 MetaboliteCHEBI:138477 (ChEBI)
18(S)-RvE3MetaboliteCHEBI:138477 (ChEBI)
18-oxo-RvE1MetaboliteCHEBI:131617 (ChEBI)
5(S)-Hp-18(R)-HEPEMetaboliteCHEBI:132908 (ChEBI)
5(S)-Hp-18(S)-HEPEMetaboliteCHEBI:132802 (ChEBI)
5-HEDHR-HSA-9022670 (Reactome)
5S,6S-epoxy-18(R)-HEPEMetaboliteCHEBI:138563 (ChEBI)
5S,6S-epoxy-18(S)-HEPEMetaboliteCHEBI:138490 (ChEBI)
ALOX15ProteinP16050 (Uniprot-TrEMBL)
ALOX5ProteinP09917 (Uniprot-TrEMBL)
Ac-PTGS2 dimerComplexR-HSA-2314687 (Reactome)
CYPR-HSA-9029001 (Reactome)
EPAMetaboliteCHEBI:28364 (ChEBI)
GPX4-2ProteinP36969-2 (Uniprot-TrEMBL)
GSHMetaboliteCHEBI:16856 (ChEBI)
GSSGMetaboliteCHEBI:17858 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HPGD ProteinP15428 (Uniprot-TrEMBL)
HPGD dimerComplexR-HSA-2142778 (Reactome)
LTA4H ProteinP09960 (Uniprot-TrEMBL)
LTA4H:Zn2+ComplexR-HSA-266038 (Reactome)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O-acetyl-L-serine-PTGS2 ProteinP35354 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PTGS2 ProteinP35354 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
heme b MetaboliteCHEBI:26355 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(18R)-resolvin E3ArrowR-HSA-9018907 (Reactome)
(18S)-hydroperoxyicosapentaenoic acidArrowR-HSA-9018874 (Reactome)
(18S)-hydroperoxyicosapentaenoic acidR-HSA-9018868 (Reactome)
(5Z,8Z,11Z,14Z,16E,18R)-18-hydroperoxyicosapentaenoic acidR-HSA-9018895 (Reactome)
18(R)-HEPEArrowR-HSA-9018895 (Reactome)
18(R)-HEPER-HSA-9018863 (Reactome)
18(R)-HEPER-HSA-9018907 (Reactome)
18(R)-RvE1,E2,E3ArrowR-HSA-9023983 (Reactome)
18(R)-RvE1,E2,E3R-HSA-9023983 (Reactome)
18(R)-RvE1ArrowR-HSA-9018877 (Reactome)
18(R)-RvE2ArrowR-HSA-9018901 (Reactome)
18(S)-HEPEArrowR-HSA-9018868 (Reactome)
18(S)-HEPER-HSA-9018858 (Reactome)
18(S)-HEPER-HSA-9020610 (Reactome)
18(S)-HpEPE, 18(R)-HpEPEArrowR-HSA-9018880 (Reactome)
18(S)-RvE1,E2,E3ArrowR-HSA-9023980 (Reactome)
18(S)-RvE1,E2,E3R-HSA-9023980 (Reactome)
18(S)-RvE1ArrowR-HSA-9018862 (Reactome)
18(S)-RvE1R-HSA-9023968 (Reactome)
18(S)-RvE2ArrowR-HSA-9018867 (Reactome)
18(S)-RvE3ArrowR-HSA-9020610 (Reactome)
18-oxo-RvE1ArrowR-HSA-9023968 (Reactome)
5(S)-Hp-18(R)-HEPEArrowR-HSA-9018863 (Reactome)
5(S)-Hp-18(R)-HEPER-HSA-9018894 (Reactome)
5(S)-Hp-18(R)-HEPER-HSA-9018901 (Reactome)
5(S)-Hp-18(S)-HEPEArrowR-HSA-9018858 (Reactome)
5(S)-Hp-18(S)-HEPER-HSA-9018859 (Reactome)
5(S)-Hp-18(S)-HEPER-HSA-9018867 (Reactome)
5-HEDHmim-catalysisR-HSA-9018867 (Reactome)
5-HEDHmim-catalysisR-HSA-9018901 (Reactome)
5S,6S-epoxy-18(R)-HEPEArrowR-HSA-9018894 (Reactome)
5S,6S-epoxy-18(R)-HEPER-HSA-9018877 (Reactome)
5S,6S-epoxy-18(S)-HEPEArrowR-HSA-9018859 (Reactome)
5S,6S-epoxy-18(S)-HEPER-HSA-9018862 (Reactome)
ALOX15mim-catalysisR-HSA-9018907 (Reactome)
ALOX15mim-catalysisR-HSA-9020610 (Reactome)
ALOX5mim-catalysisR-HSA-9018858 (Reactome)
ALOX5mim-catalysisR-HSA-9018859 (Reactome)
ALOX5mim-catalysisR-HSA-9018863 (Reactome)
ALOX5mim-catalysisR-HSA-9018894 (Reactome)
Ac-PTGS2 dimermim-catalysisR-HSA-9018880 (Reactome)
CYPmim-catalysisR-HSA-9018874 (Reactome)
EPAR-HSA-9018874 (Reactome)
EPAR-HSA-9018880 (Reactome)
GPX4-2mim-catalysisR-HSA-9018868 (Reactome)
GPX4-2mim-catalysisR-HSA-9018895 (Reactome)
GSHR-HSA-9018868 (Reactome)
GSHR-HSA-9018895 (Reactome)
GSSGArrowR-HSA-9018868 (Reactome)
GSSGArrowR-HSA-9018895 (Reactome)
H+R-HSA-9018874 (Reactome)
H2OArrowR-HSA-9018868 (Reactome)
H2OArrowR-HSA-9018895 (Reactome)
H2OR-HSA-9018862 (Reactome)
H2OR-HSA-9018877 (Reactome)
HPGD dimermim-catalysisR-HSA-9023968 (Reactome)
LTA4H:Zn2+mim-catalysisR-HSA-9018862 (Reactome)
LTA4H:Zn2+mim-catalysisR-HSA-9018877 (Reactome)
NAD+R-HSA-9023968 (Reactome)
NADHArrowR-HSA-9023968 (Reactome)
NADP+ArrowR-HSA-9018867 (Reactome)
NADP+ArrowR-HSA-9018874 (Reactome)
NADP+ArrowR-HSA-9018901 (Reactome)
NADPHR-HSA-9018867 (Reactome)
NADPHR-HSA-9018874 (Reactome)
NADPHR-HSA-9018901 (Reactome)
O2R-HSA-9018858 (Reactome)
O2R-HSA-9018859 (Reactome)
O2R-HSA-9018863 (Reactome)
O2R-HSA-9018874 (Reactome)
O2R-HSA-9018880 (Reactome)
O2R-HSA-9018894 (Reactome)
O2R-HSA-9018907 (Reactome)
O2R-HSA-9020610 (Reactome)
R-HSA-9018858 (Reactome) Unlike resolvin E3, which is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway, resolvins E1 and E2 are biosynthesised by neutrophils via the 5-lipoxygenase pathway. In neutrophils, ALOX5 oxidises 18(S)-hydroxyeicosapentaenoic acid (18(S)-HEPE) to 5(S)-hydroperoxy-18(S)-hydroxyeicosapentaenoic acid (5(S)-Hp-18(S)-HEPE) (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018859 (Reactome) In neutrophils, 5-lipoxygenase (ALOX5) can mediate the insertion of molecular oxygen into 5(S)-hydroperoxy-18(S)-hydroxyeicosapentaenoic acid (5(S)-Hp-18(S)-HEPE) to form 5S,6S-epoxy-18(S)-HEPE which is essential for 18(S)-resolvin E1 biosynthesis (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018862 (Reactome) Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 5S,6S-epoxy-18(S)-HEPE to the 18(S) stereoisomer of resolvin E1 (18(S)-RvE1) (Oh et al. 2011). The E-resolvins are anti-inflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
R-HSA-9018863 (Reactome) Unlike resolvin E3, which is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway, resolvins E1 and E2 are biosynthesised by neutrophils via the 5-lipoxygenase pathway. In neutrophils, ALOX5 oxidises 18(R)-hydroxyeicosapentaenoic acid (18(R)-HEPE) to 5(R)-hydroperoxy-18(R)-hydroxyeicosapentaenoic acid (5(R)-Hp-18(R)-HEPE) (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018867 (Reactome) An unknown dehydrogenase reduces 5(S)-hydroperoxy-18(S)-hydroxyeicosapentaenoic acid (5(S)-Hp-18(S)-HEPE) into the 18(S) stereoisomer of resolvin E2 (18(S)-RvE2). The unknown enzyme may be 5-hydroxyeicosanoid dehydrogenase (5-HEDH) or one similar to this (Patel et al. 2009). Human neutrophils biosynthesise RvE2 in greater amounts than RvE1, suggesting a significant role for RvE2 (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018868 (Reactome) In PMNs, cytosolic phospholipid hydroperoxide glutathione peroxidase (GPX4 isoform 2, GPX4-2) (Yagi et al. 1996) is a likely candidate for the reduction of organic hydroperoxides such as 18(S)-HpEPE to 18(S)-hydroxyeicosapentaenoic acid (18(S)-HEPE) (Han et al. 2013) using glutathione (GSH) as an electron donor (Brigelius-Flohe & Maiorino 2013).
R-HSA-9018874 (Reactome) The same cytochrome P450 (CYP) isoforms that metabolise the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) accept the ω-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as efficient alternative substrates (Arnold et al. 2010a). Several human CYPs are thought to oxidise EPA to 18(S)-hydroperoxyeicosapentaenoic acid (18(S)-HpEPE) although the exact CYP enzymes involved are not known (Arnold et al. 2010b, Weylandt et al. 2012). Microbial CYPs can generate 18-HEPE from EPA (Serhan et al. 2000) that can be converted by human PMNs to RvE1 and RvE2 (Arita et al. 2005). The microbial content in the local environment can therefore, also be a critical factor in the production of E-series resolvins in vivo in humans.
R-HSA-9018877 (Reactome) Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 5S,6S-epoxy-18(R)-HEPE to the 18(R) stereoisomer of resolvin E1 (18(R)-RvE1) (Oh et al. 2011). The E-resolvins are antiinflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
R-HSA-9018880 (Reactome) Normally, cyclooxygenases (COX) carry out stereospecific oxygenation of arachidonic acid to generate prostaglandins. When treated with aspirin (acetylsalicylic acid, ASA), dimeric cyclooxygenase 2 (COX2, PTGS2 dimer) can be acetylated. ASA covalently modifies PTGS2 by acetylating a serine residue at position 530 within the cyclooxygenase active site (Lucido et al. 2016). Acetylated PTGS2 dimer (Ac-PTGS2 dimer) changes the oxygenation stereospecificity towards its substrates, perhaps by steric shielding effects (Tosco 2013), producing a shift in lipid mediator production. Ac-PTGS2 dimer expressed in neutrophils can be acetylated by ASA, which now switches to mediate biosynthesis of precursors of endogenous antiinflammatory mediators. Ac-PTGS2 dimer is able to incorporate molecular oxygen into eicosapentaenoic acid (EPA) to form the stereoisomers 18(S)- and 18(R)-hydroperoxy-eicosapentaenoic acid (18(S)- and 18(R)-HpEPE respectively) (Serhan et al. 2000, Oh et al. 2011).
R-HSA-9018894 (Reactome) In neutrophils, 5-lipoxygenase (ALOX5) can mediate the insertion of molecular oxygen into 5(S)-hydroperoxy-18(R)-hydroxyeicosapentaenoic acid (5(S)-Hp-18(R)-HEPE) to form 5S,6S-epoxy-18(R)-HEPE which is essential for 18(R)-resolvin E1 biosynthesis (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018895 (Reactome) In PMNs, cytosolic phospholipid hydroperoxide glutathione peroxidase (GPX4 isoform 2, GPX4-2) (Yagi et al. 1996) is a likely candidate for the reduction of organic hydroperoxides such as 18(R)-HpEPE to 18(R)-hydroxyeicosapentaenoic acid (18(R)-HEPE) (Han et al. 2013) using glutathione (GSH) as an electron donor (Brigelius-Flohe & Maiorino 2013).
R-HSA-9018901 (Reactome) An unknown dehydrogenase reduces 5(S)-hydroperoxy-18(R)-hydroxyeicosapentaenoic acid (5(S)-Hp-18(R)-HEPE) into the 18(R) stereoisomer of resolvin E2 (18(R)-RvE2). The unknown enzyme may be 5-hydroxyeicosanoid dehydrogenase (5-HEDH) or one similar to this (Patel et al. 2009). Human neutrophils biosynthesise RvE2 in greater amounts than RvE1, suggesting a significant role for RvE2 (Tjonahen et al. 2006, Oh et al. 2012).
R-HSA-9018907 (Reactome) Unlike resolvins E1 and E2, both of which are biosynthesised by neutrophils via the 5-lipoxygenase pathway, resolvin E3 (RvE3) is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway. 18(R)-hydroxyeicosapentaenoic acid (18(R)-HEPE) is oxidised by ALOX15 (possibly through C13-hydrogen abstraction) into a number of dihydroxy-HEPEs including 17(R),18(R)-diHEPE (18(R)-RvE3) (Isobe et al. 2012, Isobe et al. 2013).
R-HSA-9020610 (Reactome) Unlike resolvins E1 and E2, both of which are biosynthesised by neutrophils via the 5-lipoxygenase pathway, resolvin E3 (RvE3) is biosynthesised in eosinophils or resident macrophages via the 15-lipoxygenase (ALOX15) pathway. 18(S)-hydroxyeicosapentaenoic acid (18(S)-HEPE) is oxidised by ALOX15 (possibly through C13-hydrogen abstraction) into a number of dihydroxy-HEPEs including 17(R),18(S)-diHEPE (18(S)-RvE3) (Isobe et al. 2012, Isobe et al. 2013).
R-HSA-9023968 (Reactome) In human blood, the major metabolic products of RvE1 are 10,11-dihydro-RvE1, 18-oxo-RvE1, and 20-hydroxy-RvE1 (Hong et al. 2008). 18-oxo-RvE1, formed by dimeric 15-hydroxyprostaglandin dehydrogenase (HPGD dimer) in the presence of NAD+, is also the major metabolite formed in murine lung and has been demonstrated to be devoid of activity, representing a mode of RvE1 inactivation (Arita et al. 2006). The exact enzymes that catalyze the formation of the other RvE1 metabolites mentioned here are currently unknown.
R-HSA-9023980 (Reactome) To produce their pro-resolving effects, 18(S)-RvE1, E2 and E3 are released into the exudate of local inflammation sites (Serhan et al. 2000). The mechanism of translocation is unknown.
R-HSA-9023983 (Reactome) To produce their pro-resolving effects, 18(R)-RvE1, E2 and E3 are released into the exudate of local inflammation sites (Serhan et al. 2000). The mechanism of translocation is unknown.
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