Biosynthesis of DPA-derived SPMs (Homo sapiens)

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2, 5, 12, 1462, 666122, 61, 62, 63, 8, 9, 12, 132, 63, 9, 124, 114, 11666, 15, 166, 15, 164, 1110, 1166, 15, 16cytosolNeutrophilVascular endothelial cellcytosolALOX5ALOX12:Fe2+RvD2n-3DPA MaR3n-3 DPADPAn-3 maresins16(S),17(S)-epoxy-DPAn-310(S),17(S)-dihydroxy-omega 6-docosapentaenoic acid 13(R)-HDPAn-310(S),17(S)-dihydroxy-omega 6-docosapentaenoic acid ALOX15MaR1n-3 DPA, MaR2n-3 DPA MaR3n-3 DPA H2ODPAn-6 SPMs17(S)-Hp-DPAn-3O2MaR1n-3 DPA, MaR2n-3 DPA PD2n-3DPA O213(R)-HDPAn-3ALOX12 RvD5n-3DPARvT3 PTGS2 dimer10(S),17(S)-diHDPAn-6 H2OO2O2DPAn-3 resolvinsPD1n-3DPA,PD2n-3DPARvT2 DPAn-3 maresinsRvD5n-3DPA (4Z,7Z,10Z,13Z,15E,17S)-17-hydroxydocosapentaenoic acid RvT4 reduced acceptorMaR1n-3 DPA, MaR2n-3DPARvT1 RvD1n-3DPA,RvD2n-3DPA14(S)-HDPAn-6 NADP+DPAn-3 resolvinsRvT1-413,14(S)-epoxy-DPAn-3PTGS2 MaR1n-3 DPA RvD1n-3DPA 17(S)-HDPAn-6 HydroperoxyreductaseRvD5n-3DPA RvT3 NADPHNADPHRvT2 PD1n-3DPA,PD2n-3DPANADP+RvD2n-3DPA 14(S)-Hp-DHADPAn-314(S)-HDPAn-6 7,8-epoxy,17-HDPAn-3Fe2+ ALOX15PD1n-3DPA RvT4 PD1n-3DPA 14(S)-HDPAn-6RvD2n-3DPA Epoxide hydrolaseRvD1n-3DPA O2(4Z,7Z,10Z,13Z,15E,17S)-17-hydroxydocosapentaenoic acid ALOX57,17-diHp-DPAn-3NADPH14(S)-Hp-DPAn-3DPAn-617(S)-HDPAn-6,10(S),17(S)-diHDPAn-6MaR3n-3 DPA RvT1 RvT1-4DPAn-6 SPMsPD2n-3DPA MaR2n-3 DPA NADP+H2ORvD1n-3DPA oxidised acceptorheme b 7


Description

Docosapentaenoic acid (DPA), a C22:5 long-chain ω3 or ω6 polyunsaturated fatty acid (PUFA), is found in algal and fish oils, created via linoleic acid metabolism and is a metabolite in DHA metabolism. It can be acted upon by lipoxygenases to produce mono-, di- and tri-hydroxy derivatives in neutrophils and macrophages. These DPA derivatives are another branch of the specialised proresolving mediators (SPMs) produced from long-chain fatty acids which have anti-inflammatory properties, even though mechanisms of their anti-inflammatory action have not been fully elucidated (Bannenberg & Serhan 2010, Dangi et al. 2010, Vik et al. 2017, Hansen et al. 2017).

The biosynthesis of SPMs derived from the two isomers of DPA, DPAn-6 (cis-4,7,10,13,16-docosapentaenoic acid) and DPAn-3 (cis-7,10,13,16,19-docosapentaenoic acid), is described here. The only difference between the two isomers is the position of the first double bond; ω-3 for DPAn-3 and ω-6 for DPAn-6. The products of these isomers were characterised by analogy in structure and action to docosahexaenoic acid (DHA)-derived and eicosapentaenoic acid (EPA)-derived resolvins, protectins and maresins (Serhan et al. 2002, Bannenberg & Serhan 2010, Serhan et al. 2015). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9018683
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Tungen JE, Aursnes M, Dalli J, Arnardottir H, Serhan CN, Hansen TV.; ''Total synthesis of the anti-inflammatory and pro-resolving lipid mediator MaR1n-3 DPA utilizing an sp(3) -sp(3) Negishi cross-coupling reaction.''; PubMed Europe PMC
  2. Vik A, Dalli J, Hansen TV.; ''Recent advances in the chemistry and biology of anti-inflammatory and specialized pro-resolving mediators biosynthesized from n-3 docosapentaenoic acid.''; PubMed Europe PMC
  3. Dangi B, Obeng M, Nauroth JM, Teymourlouei M, Needham M, Raman K, Arterburn LM.; ''Biogenic synthesis, purification, and chemical characterization of anti-inflammatory resolvins derived from docosapentaenoic acid (DPAn-6).''; PubMed Europe PMC
  4. Primdahl KG, Aursnes M, Walker ME, Colas RA, Serhan CN, Dalli J, Hansen TV, Vik A.; ''Synthesis of 13(R)-Hydroxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins.''; PubMed Europe PMC
  5. Bannenberg G, Serhan CN.; ''Specialized pro-resolving lipid mediators in the inflammatory response: An update.''; PubMed Europe PMC
  6. Dalli J, Colas RA, Serhan CN.; ''Novel n-3 immunoresolvents: structures and actions.''; PubMed Europe PMC
  7. 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
  8. Dayaker G, Durand T, Balas L.; ''Total synthesis of neuroprotectin D1 analogues derived from omega-6 docosapentaenoic acid (DPA) and adrenic acid (AdA) from a common pivotal, late-stage intermediate.''; PubMed Europe PMC
  9. Dobson EP, Barrow CJ, Kralovec JA, Adcock JL.; ''Controlled formation of mono- and dihydroxy-resolvins from EPA and DHA using soybean 15-lipoxygenase.''; PubMed Europe PMC
  10. Walker ME, Souza PR, Colas RA, Dalli J.; ''13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis.''; PubMed Europe PMC
  11. Dalli J, Chiang N, Serhan CN.; ''Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections.''; PubMed Europe PMC
  12. Dangi B, Obeng M, Nauroth JM, Chung G, Bailey-Hall E, Hallenbeck T, Arterburn LM.; ''Metabolism and biological production of resolvins derived from docosapentaenoic acid (DPAn-6).''; PubMed Europe PMC
  13. Nauroth JM, Liu YC, Van Elswyk M, Bell R, Hall EB, Chung G, Arterburn LM.; ''Docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-6) algal oils reduce inflammatory mediators in human peripheral mononuclear cells in vitro and paw edema in vivo.''; PubMed Europe PMC
  14. Hansen TV, Dalli J, Serhan CN.; ''The novel lipid mediator PD1n-3 DPA: An overview of the structural elucidation, synthesis, biosynthesis and bioactions.''; PubMed Europe PMC
  15. Primdahl KG, Tungen JE, De Souza PRS, Colas RA, Dalli J, Hansen TV, Vik A.; ''Stereocontrolled synthesis and investigation of the biosynthetic transformations of 16(S),17(S)-epoxy-PDn-3 DPA.''; PubMed Europe PMC
  16. Aursnes M, Tungen JE, Vik A, Colas R, Cheng CY, Dalli J, Serhan CN, Hansen TV.; ''Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
102033view16:19, 26 November 2018Marvin M2Ontology Term : 'PW:0000029' removed !
102032view16:19, 26 November 2018Marvin M2Ontology Term : 'unsaturated fatty acid biosynthetic pathway' added !
101697view14:32, 1 November 2018DeSlchanged weird symbols
101696view14:30, 1 November 2018DeSlOntology Term : 'fatty acid biosynthetic pathway' added !
101492view11:36, 1 November 2018ReactomeTeamreactome version 66
101029view21:16, 31 October 2018ReactomeTeamreactome version 65
100726view20:11, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
(4Z,7Z,10Z,13Z,15E,17S)-17-hydroxydocosapentaenoic acid MetaboliteCHEBI:138673 (ChEBI)
10(S),17(S)-diHDPAn-6 MetaboliteCHEBI:138674 (ChEBI)
10(S),17(S)-dihydroxy-omega 6-docosapentaenoic acid MetaboliteCHEBI:138674 (ChEBI)
13(R)-HDPAn-3MetaboliteCHEBI:91274 (ChEBI)
13,14(S)-epoxy-DPAn-3MetaboliteCHEBI:140200 (ChEBI)
14(S)-HDPAn-6 MetaboliteCHEBI:140218 (ChEBI)
14(S)-HDPAn-6MetaboliteCHEBI:140218 (ChEBI)
14(S)-Hp-DHAMetaboliteCHEBI:140220 (ChEBI)
14(S)-Hp-DPAn-3MetaboliteCHEBI:140222 (ChEBI)
16(S),17(S)-epoxy-DPAn-3MetaboliteCHEBI:140224 (ChEBI)
17(S)-HDPAn-6 MetaboliteCHEBI:138673 (ChEBI)
17(S)-HDPAn-6, 10(S),17(S)-diHDPAn-6ComplexR-ALL-9025151 (Reactome)
17(S)-Hp-DPAn-3MetaboliteCHEBI:140226 (ChEBI)
7,17-diHp-DPAn-3MetaboliteCHEBI:140248 (ChEBI)
7,8-epoxy,17-HDPAn-3MetaboliteCHEBI:140234 (ChEBI)
ALOX12 ProteinP18054 (Uniprot-TrEMBL)
ALOX12:Fe2+ComplexR-HSA-2142793 (Reactome)
ALOX15ProteinP16050 (Uniprot-TrEMBL)
ALOX5ProteinP09917 (Uniprot-TrEMBL)
DPAn-3 maresinsComplexR-ALL-9031885 (Reactome)
DPAn-3 maresinsComplexR-ALL-9031900 (Reactome)
DPAn-3 resolvinsComplexR-ALL-9031889 (Reactome)
DPAn-3 resolvinsComplexR-ALL-9031890 (Reactome)
DPAn-3MetaboliteCHEBI:53488 (ChEBI)
DPAn-6 SPMsComplexR-ALL-9031892 (Reactome)
DPAn-6 SPMsComplexR-ALL-9031904 (Reactome)
DPAn-6MetaboliteCHEBI:65136 (ChEBI)
Epoxide hydrolaseR-HSA-9025025 (Reactome)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
Hydroperoxy reductaseR-HSA-9024779 (Reactome)
MaR1n-3 DPA MetaboliteCHEBI:140256 (ChEBI)
MaR1n-3 DPA, MaR2n-3 DPAComplexR-ALL-9026321 (Reactome)
MaR1n-3 DPA, MaR2n-3 DPA R-ALL-9026321 (Reactome)
MaR1n-3 DPA, MaR2n-3 DPA R-ALL-9031887 (Reactome)
MaR2n-3 DPA MetaboliteCHEBI:140257 (ChEBI)
MaR3n-3 DPA MetaboliteCHEBI:140258 (ChEBI)
MaR3n-3 DPAMetaboliteCHEBI:140258 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PD1n-3DPA MetaboliteCHEBI:140265 (ChEBI)
PD1n-3DPA,PD2n-3DPAComplexR-ALL-9026023 (Reactome)
PD1n-3DPA,PD2n-3DPAComplexR-ALL-9031899 (Reactome)
PD2n-3DPA MetaboliteCHEBI:140266 (ChEBI)
PTGS2 ProteinP35354 (Uniprot-TrEMBL)
PTGS2 dimerComplexR-HSA-140491 (Reactome)
RvD1n-3DPA MetaboliteCHEBI:140271 (ChEBI)
RvD1n-3DPA, RvD2n-3DPAComplexR-ALL-9026291 (Reactome)
RvD2n-3DPA MetaboliteCHEBI:140272 (ChEBI)
RvD5n-3DPA MetaboliteCHEBI:140273 (ChEBI)
RvD5n-3DPAMetaboliteCHEBI:140273 (ChEBI)
RvT1 MetaboliteCHEBI:137011 (ChEBI)
RvT1-4ComplexR-ALL-9026394 (Reactome)
RvT1-4ComplexR-ALL-9032020 (Reactome)
RvT2 MetaboliteCHEBI:137018 (ChEBI)
RvT3 MetaboliteCHEBI:137019 (ChEBI)
RvT4 MetaboliteCHEBI:137020 (ChEBI)
heme b MetaboliteCHEBI:26355 (ChEBI)
oxidised acceptorR-ALL-9024637 (Reactome)
reduced acceptorR-ALL-5359016 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
13(R)-HDPAn-3ArrowR-HSA-9026408 (Reactome)
13(R)-HDPAn-3ArrowR-HSA-9026411 (Reactome)
13(R)-HDPAn-3R-HSA-9026405 (Reactome)
13(R)-HDPAn-3R-HSA-9026411 (Reactome)
13,14(S)-epoxy-DPAn-3ArrowR-HSA-9026007 (Reactome)
13,14(S)-epoxy-DPAn-3R-HSA-9025998 (Reactome)
14(S)-HDPAn-6ArrowR-HSA-9025957 (Reactome)
14(S)-Hp-DHAR-HSA-9026007 (Reactome)
14(S)-Hp-DPAn-3ArrowR-HSA-9026006 (Reactome)
14(S)-Hp-DPAn-3R-HSA-9026005 (Reactome)
16(S),17(S)-epoxy-DPAn-3ArrowR-HSA-9025999 (Reactome)
16(S),17(S)-epoxy-DPAn-3R-HSA-9026000 (Reactome)
17(S)-HDPAn-6, 10(S),17(S)-diHDPAn-6ArrowR-HSA-9025152 (Reactome)
17(S)-Hp-DPAn-3ArrowR-HSA-9026003 (Reactome)
17(S)-Hp-DPAn-3R-HSA-9025996 (Reactome)
17(S)-Hp-DPAn-3R-HSA-9025999 (Reactome)
7,17-diHp-DPAn-3ArrowR-HSA-9025996 (Reactome)
7,17-diHp-DPAn-3R-HSA-9025995 (Reactome)
7,17-diHp-DPAn-3R-HSA-9026001 (Reactome)
7,8-epoxy,17-HDPAn-3ArrowR-HSA-9025995 (Reactome)
7,8-epoxy,17-HDPAn-3R-HSA-9026008 (Reactome)
ALOX12:Fe2+mim-catalysisR-HSA-9025957 (Reactome)
ALOX12:Fe2+mim-catalysisR-HSA-9026006 (Reactome)
ALOX12:Fe2+mim-catalysisR-HSA-9026007 (Reactome)
ALOX15mim-catalysisR-HSA-9025152 (Reactome)
ALOX15mim-catalysisR-HSA-9026003 (Reactome)
ALOX5mim-catalysisR-HSA-9025995 (Reactome)
ALOX5mim-catalysisR-HSA-9025996 (Reactome)
ALOX5mim-catalysisR-HSA-9025999 (Reactome)
ALOX5mim-catalysisR-HSA-9026005 (Reactome)
ALOX5mim-catalysisR-HSA-9026405 (Reactome)
DPAn-3 maresinsArrowR-HSA-9031894 (Reactome)
DPAn-3 maresinsR-HSA-9031894 (Reactome)
DPAn-3 resolvinsArrowR-HSA-9031881 (Reactome)
DPAn-3 resolvinsR-HSA-9031881 (Reactome)
DPAn-3R-HSA-9026003 (Reactome)
DPAn-3R-HSA-9026006 (Reactome)
DPAn-3R-HSA-9026408 (Reactome)
DPAn-6 SPMsArrowR-HSA-9031884 (Reactome)
DPAn-6 SPMsR-HSA-9031884 (Reactome)
DPAn-6R-HSA-9025152 (Reactome)
DPAn-6R-HSA-9025957 (Reactome)
Epoxide hydrolasemim-catalysisR-HSA-9025998 (Reactome)
Epoxide hydrolasemim-catalysisR-HSA-9026000 (Reactome)
Epoxide hydrolasemim-catalysisR-HSA-9026008 (Reactome)
H2OR-HSA-9025998 (Reactome)
H2OR-HSA-9026000 (Reactome)
H2OR-HSA-9026008 (Reactome)
Hydroperoxy reductasemim-catalysisR-HSA-9026001 (Reactome)
MaR1n-3 DPA, MaR2n-3 DPAArrowR-HSA-9025998 (Reactome)
MaR3n-3 DPAArrowR-HSA-9026005 (Reactome)
NADP+R-HSA-9025995 (Reactome)
NADP+R-HSA-9025999 (Reactome)
NADP+R-HSA-9026007 (Reactome)
NADPHArrowR-HSA-9025995 (Reactome)
NADPHArrowR-HSA-9025999 (Reactome)
NADPHArrowR-HSA-9026007 (Reactome)
O2R-HSA-9025152 (Reactome)
O2R-HSA-9025957 (Reactome)
O2R-HSA-9025996 (Reactome)
O2R-HSA-9026003 (Reactome)
O2R-HSA-9026005 (Reactome)
O2R-HSA-9026006 (Reactome)
O2R-HSA-9026405 (Reactome)
O2R-HSA-9026408 (Reactome)
PD1n-3DPA,PD2n-3DPAArrowR-HSA-9026000 (Reactome)
PD1n-3DPA,PD2n-3DPAArrowR-HSA-9031896 (Reactome)
PD1n-3DPA,PD2n-3DPAR-HSA-9031896 (Reactome)
PTGS2 dimermim-catalysisR-HSA-9026408 (Reactome)
R-HSA-9025152 (Reactome) Of the 5-, 12- and 15-lipoxygenases, 15-lipoxygenase is the most efficient enzyme in oxygenating docosapentaenoic acids DPAn-6 and DPAn-3 as well as docosahexaenoic acid (DHA) at efficiencies 100%, 85% and 50% respectively. The main products of DPAn-6 oxygenation were found to be 17(S)-hydroxy-DPAn-6 and (10(S),17(S)-dihydroxy-DPAn-6 (17(S)-HDPAn-6 and 10(S),17(S)-diHDPAn-6 respectively) (Dangi et al. 2009, 2010, Dobson et al. 2013, Dayaker et al. 2014). Tested in two animal models of acute inflammation (Dangi et al. 2010) and human peripheral mononuclear cells (Nauroth et al. 2010), both compounds possessed potent anti-inflammatory activity. These DPAn-6 products are analogous in structure and action to DHA (docosahexaenoic acid)-derived resolvins (Dangi et al. 2010).
R-HSA-9025957 (Reactome) The main product of ω-6 docosapentaenoic acid (DPAn-6) oxygenation by 12-lipoxygenase (ALOX12:Fe2+) is 14(S)-hydroxy-DPAn-6 (14(S)-HDPAn-6) (Dangi et al. 2009, 2010, Dobson et al. 2013). The final product is produced via a hydroperoxy intermediate, which is then reduced to the corresponding hydroxy compound (these details not described here and also, the human enzymes involved in these reactions are unknown). This DPAn-6 product is analogous in structure and action to DHA (docosahexaenoic acid)-derived resolvins (Dangi et al. 2010).
R-HSA-9025995 (Reactome) Instead of the dihydroperoxy intermediate being reduced, a lipoxygenase may mediate hydrogen abstraction from 7,17-dihydroperoxy-docosapentaenoic acid (7,17-diHp-DPAn-3) to form 7,8-epoxy, 17-hydroxydocosapentaenoic acid (7,8-epoxy,17-HDPAn-3) (Dalli et al. 2013). Although this is a proposed biosynthetic route for the formation of DPA-n-3 resolvins, it is assumed DPAn-3-derived SPMs follow a similar synthesis route to DHA- and EPA-derived SPMs and therefore, the lipoxygenase could be the dual-functional 5-lipoxygenase (ALOX5).
R-HSA-9025996 (Reactome) In an alternative route to the production of protectins PD1n-3DPA and PD2n-3DPA, 17(S)-hydroperoxy-docosapentaenoic acid (17(S)-Hp-DPAn-3) can be further oxygenated by a lipoxygenase to form 7,17-dihydroperoxy-docosapentaenoic acid (7,17-diHp-DPAn-3) (Dalli et al. 2013). Although this is a proposed biosynthetic route, it is assumed DPAn-3-derived SPMs follow a similar synthesis route to DHA- and EPA-derived SPMs therefore the lipoxygenase could be the dual-functional 5-lipoxygenase (ALOX5).
R-HSA-9025998 (Reactome) In a reaction scheme similar to the one for DHA-derived maresins, 13,14(S)-epoxy-docosapentaenoic acid (13,14(S)-epoxy-DPAn-3) can be hydrolysed by an epoxide hydrolase to form either 7(R),14(S)-dihydroxy-docosapentaenoic acid (MaR1n-3 DPA) or 13,14(S)-dihydroxy-docosapentaenoic acid (MaR2n-3 DPA) (Dalli et al. 2013). MaR1n-3 DPA and MaR2n-3 DPA are named after maresin-1 (derived from DHA) as they share an alcohol group at C14 and are proposed to possess similar anti-inflammatory and proresolving potency and activity as maresin-1. With human leukocytes these n-3 DPA-SPMs reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis (Dalli et al. 2013, Vik et al. 2017). The total chemical synthesis of MaR1n-3 DPA had been reported for the first time in 2014 (Tungen et al. 2014).
R-HSA-9025999 (Reactome) In neutrophils, an unknown lipoxygenase may mediate hydrogen abstraction from 17(S)-hydroperoxy-docosapentaenoic acid (17(S)-Hp-DPAn-3) to form 16(S),17(S)-epoxy-docosapentaenoic acid (16(S),17(S)-epoxy-DPAn-3) (Dalli et al. 2013). If, as assumed, DPA metabolism follows the same path as DHA metabolism, the lipoxygenase could be the dual-functional 5-lipoxygenase (ALOX5). The formation of this epoxy intermediate is supported by chemical synthesis experiments (Aursnes et al. 2014, Primdahl et al. 2017).
R-HSA-9026000 (Reactome) In neutrophils, an epoxide hydrolase can hydrolyse 16(S),17(S)-epoxy-docosapentaenoic acid (16(S),17(S)-epoxy-DPAn-3) to either 10(R),17(S)-dihydroxy-docosapentaenoic acid (PD1n-3DPA) or 16,17(S)-dihydroxy-docosapentaenoic acid (PD2n-3DPA) (Dalli et al. 2013). The formation of these protectins is supported by chemical synthesis experiments (Aursnes et al. 2014, Primdahl et al. 2017). These DPAn-3-derived protectins demonstrate potent anti-inflammatory activities together with pro-resolving actions, stimulating human macrophage phagocytosis and efferocytosis (Dalli et al. 2013, Aursnes et al. 2014, Primdahl et al. 2017, Gobbetti et al. 2017).
R-HSA-9026001 (Reactome) A hydroperoxy reductase probably reduces 7,17-dihydroperoxy-docosapentaenoic acid (7,17-diHp-DPAn-3) to the resolvin 7,17-dihydroxy-docosapentaenoic acid (RvD5n-3DPA) (Dalli et al. 2013). Treatment with RvD5n-3DPA reduced colitis and intestinal ischemia/reperfusion-induced inflammation in mice and reduced human neutrophil-endothelial cell interactions with TNF-α-activated human endothelial monolayers (Gobbetti et al. 2017). Although this is a proposed biosynthetic route for the formation of DPA-n-3 resolvins, it is assumed DPAn-3-derived SPMs follow a similar synthesis route to DHA- and EPA-derived SPMs.
R-HSA-9026003 (Reactome) At sites of injury, 15 lipoxygenase (ALOX15) can oxygenate ω-3 docosapentaenoic acid (DPAn-3) to form the 17(S) epimer 17(S)-hydroperoxy docosapentaenoic acid (17(S)-Hp-DPAn-3) in neutrophils (Dalli et al. 2013). The formations of individual hydroperoxy intermediates are supported by chemical synthesis experiments (Aursnes et al. 2014, Primdahl et al. 2017) and are the pivotal intermediates in the production of DPAn-3 derived protectins and resolvins.
R-HSA-9026005 (Reactome) In an alternative reaction to epoxidation, 14(S)-hydroperoxy-docosapentaenoic acid (14(S)-HpDPAn-3) can undergo a second oxygenation at the ω-1 position to yield 14(S), 21-dihydroxy-docosapentaenoic acid (MaR3n-3 DPA) (Dalli et al. 2013). MaR3n-3 DPA is named after maresin-1 (derived from DHA) as they share an alcohol group at C14 and is proposed to possess similar anti-inflammatory and proresolving potency and activity as maresin-1. With human leukocytes this n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis (Dalli et al. 2013, Vik et al. 2017). If, as assumed, DPA metabolism follows the same path as DHA metabolism, the lipoxygenase could be the dual-functional 5-lipoxygenase (ALOX5).
R-HSA-9026006 (Reactome) In a parallel pathway to 15-lipoxygenase-initiated protectin formation from ω-3 docosapentaenoic acid (DPAn-3), 12-lipoxygenase can also oxygenate DPAn-3 to form 14(S)-hydroperoxy-docosapentaenoic acid (14(S)-Hp-DPAn-3) (Dalli et al. 2013). This intermediate is the precursor for DPA-n-3-derived maresins.
R-HSA-9026007 (Reactome) In a reaction scheme that could be similar to the one for DHA-derived maresins, a lipoxygenase mediates the abstraction of hydrogen from 14(S)-hydroperoxy-docosapentaenoic acid (14(S)-Hp-DPAn-3) to form the epoxy product 13,14(S)-epoxy-docosapentaenoic acid (13,14(S)-epoxy-DPAn-3) (Dalli et al. 2013). If, as assumed, DPA metabolism follows the same path as for DHA metabolism, the lipoxygenase could be 12-lipoxygenase (ALOX12).
R-HSA-9026008 (Reactome) In neutrophils, an epoxide hydrolase is thought to hydrolyse 7,8-epoxy-17-hydroxydocosapentaenoic acid (7,8-epoxy-HDPAn-3) to either of the resolvins 7,8,17-trihydroxy-docosapentaenoic acid (RvD1n-3DPA) or 7,16,17-trihydroxy-docosapentaenoic acid (RvD2n-3DPA) (Dalli et al. 2013). Treatment of induced inflammation in mice with RvD1n-3DPA and RvD2n-3DPA reduced neutrophil infiltration and adhesion and enhanced macrophage phagocytosis; all key steps in inflammatory resolution (Dalli et al. 2013, Gobbetti et al. 2017). Although this is a proposed biosynthetic route for the formation of DPA-n-3 resolvins, it is assumed DPAn-3-derived SPMs follow a similar synthesis route to DHA- and EPA-derived SPMs.
R-HSA-9026405 (Reactome) In neutrophils, 5-lipoxygenase (ALOX5) oxidises 13(R)-hydroxy-docosapentaenoic acid (13(R)-DPAn-3) to the 13(R)-resolvins RvT1-4 (7,13,20-trihydroxy-docosapentaenoic acid, 7,12,13-trihydroxy-docosapentaenoic acid, 7,8,13-trihydroxy-docosapentaenoic acid and 7,13-dihydroxy-docosapentaenoic acid respectively) (Dalli et al. 2015, Primdahl et al. 2016). They were all shown to posses anti-inflammatory and proresolving activities (Dalli et al. 2015). Recently, RvTs have been shown to mediate the proresolving actions of several statins in mice with inflammatory arthritis (Walker et al. 2017).
R-HSA-9026408 (Reactome) Incubation of ω-3 docosapentaenoic acid (DPAn-3) with human recombinant cyclooxygenase 2 (PTGS2 dimer, COX2) in vascular endothelial cells produces 13(R)-hydroxy-docasapentaenoic acid (13(R)-HDPAn-3), the precursor of 13(R)-resolvins and the electrophilic 13-oxo-DPAn-3 (Dalli et al. 2015, Primdahl et al. 2016).
R-HSA-9026411 (Reactome) 13(R)-hydroxy-docosapentaenoic acid (13(R)-DPAn-3) translocates from endothelial cells to adhered neutrophils, where it can be oxidised further (Dalli et al. 2015, Primdahl et al. 2016).
R-HSA-9031881 (Reactome) To produce their pro-resolving effects, DPAn-3 derived resolvins (RvD1n-3DPA, RvD2n-3DPA and RvD5n-3DPA) are released into the exudate of local inflammation sites (Dalli et al. 2013, Vik et al. 2017). The mechanism of translocation is unknown.
R-HSA-9031884 (Reactome) To produce their pro-resolving effects, DPAn-6 SPMs are released into the exudate of local inflammation sites (Dangi et al. 2010). The mechanism of translocation is unknown.
R-HSA-9031894 (Reactome) To produce their pro-resolving effects, DPAn-3 derived maresins (MaR1n-3DPA, MaR2n-3DPA and MaR3n-3DPA) are released into the exudate of local inflammation sites (Dalli et al. 2013, Vik et al. 2017). The mechanism of translocation is unknown.
R-HSA-9031896 (Reactome) To produce their pro-resolving effects, DPAn-3 derived protectins (PD1n-3 and PD2n-3) are released into the exudate of local inflammation sites (Dalli et al. 2013, Vik et al. 2017). The mechanism of translocation is unknown.
R-HSA-9032021 (Reactome) To produce their pro-resolving effects, 13(R)-resolvins RvT1-4 are released into the exudate of local inflammation sites (Dalli et al. 2015, Walker et al. 2017). The mechanism of translocation is unknown.
RvD1n-3DPA, RvD2n-3DPAArrowR-HSA-9026008 (Reactome)
RvD5n-3DPAArrowR-HSA-9026001 (Reactome)
RvT1-4ArrowR-HSA-9026405 (Reactome)
RvT1-4ArrowR-HSA-9032021 (Reactome)
RvT1-4R-HSA-9032021 (Reactome)
oxidised acceptorArrowR-HSA-9026001 (Reactome)
reduced acceptorR-HSA-9026001 (Reactome)
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