Synthesis of Lipoxins (LX) (Homo sapiens)

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1, 3, 1511, 16, 17124, 8121082, 5, 13, 147, 9, 13cytosolcytosolPlateletNeutrophilnuclear envelopeLXB4 Fe2+ PTGR1O2HPGD dimerNADPHLXA4/B4LTC4S NADP+ALOX12 LXA4 LXA4 ALOX5AP HPGD NADHLXA4/B4LTA4LXA4 H+LXB4 15R-HETEFe2+ O2NAD+dhk-LXA4LXA4 p-S272-ALOX5 H+15epi-LXB4 15S-HpETEALOX12:Fe2+15epi-LXA4/B4LXA4/B4LXB4 LTA4H2O15epi-LXA4 Ca2+ LXA4ALOX5:ALOX5AP:LTC4SLXA4/B4LXB4 15k-LXA45S-HpETE6


Description

Lipoxins A4 (LXA4) and B4 (LXB4), structurally characterized from human neutrophils incubated with 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), each contain three hydroxyl moieties and a conjugated tetraene. The third hydroxyl of LXA4 is positioned at C-6, and of LXB4 at C-14. The action of arachidonate 5-lipoxygenase (ALOX5), in concert with an arachidonate 12-lipoxygenase (ALOX12) or arachidonate 15-lipoxygenase (ALOX15) activity, has been shown to produce lipoxins by three distinct pathways. Neutrophil ALOX5 can produce and secrete leukotriene A4 (LTA4) that is taken up by platelets, where it is acted upon by ALOX12 to form lipoxins. Likewise, ALOX15s can generate either 15-hydroperoxy-eicosatetraenoic acid (15-HpETE) or 15-hydro-eicosatetraenoic acid (15-HETE) that can be taken up by monocytes and neutrophils, where highly expressed ALOX5 uses it to generate lipoxins. Finally, aspirin acetylated prostaglandin G/H synthase 2 (PTGS2), rendered unable to synthesize prostaglandins, can act as a 15-lipoxygenase. This leads to the formation of 15R-HETE and culminates in creation of epi-lipoxins, which have altered stereochemistry at the C-15 hydroxyl but similar biological potency (Chiang et al. 2006, Buczynski et al. 2009, Vance & Vance 2008, Stsiapanava et al. 2017). View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 2142700
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: Williams, MG

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Bibliography

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  1. Serhan CN, Hamberg M, Samuelsson B.; ''Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes.''; PubMed Europe PMC Scholia
  2. Clària J, Serhan CN.; ''Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.''; PubMed Europe PMC Scholia
  3. Stsiapanava A, Samuelsson B, Haeggström JZ.; ''Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis.''; PubMed Europe PMC Scholia
  4. Rouzer CA, Matsumoto T, Samuelsson B.; ''Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities.''; PubMed Europe PMC Scholia
  5. Serhan CN, Hamberg M, Samuelsson B.; ''Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes.''; PubMed Europe PMC Scholia
  6. Samuelsson B, Dahlén SE, Lindgren JA, Rouzer CA, Serhan CN.; ''Leukotrienes and lipoxins: structures, biosynthesis, and biological effects.''; PubMed Europe PMC Scholia
  7. Chiang N, Serhan CN, Dahlén SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C.; ''The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.''; PubMed Europe PMC Scholia
  8. Buczynski MW, Dumlao DS, Dennis EA.; ''Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology.''; PubMed Europe PMC Scholia
  9. Romano M, Chen XS, Takahashi Y, Yamamoto S, Funk CD, Serhan CN.; ''Lipoxin synthase activity of human platelet 12-lipoxygenase.''; PubMed Europe PMC Scholia
  10. Serhan CN, Sheppard KA.; ''Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro.''; PubMed Europe PMC Scholia
  11. Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN.; ''Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation.''; PubMed Europe PMC Scholia
  12. Rouzer CA, Rands E, Kargman S, Jones RE, Register RB, Dixon RA.; ''Characterization of cloned human leukocyte 5-lipoxygenase expressed in mammalian cells.''; PubMed Europe PMC Scholia
  13. Puustinen T, Webber SE, Nicolaou KC, Haeggström J, Serhan CN, Samuelsson B.; ''Evidence for a 5(6)-epoxytetraene intermediate in the biosynthesis of lipoxins in human leukocytes. Conversion into lipoxin A by cytosolic epoxide hydrolase.''; PubMed Europe PMC Scholia
  14. Ueda N, Yamamoto S, Fitzsimmons BJ, Rokach J.; ''Lipoxin synthesis by arachidonate 5-lipoxygenase purified from porcine leukocytes.''; PubMed Europe PMC Scholia
  15. Strid T, Svartz J, Franck N, Hallin E, Ingelsson B, Söderström M, Hammarström S.; ''Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein.''; PubMed Europe PMC Scholia
  16. Rouzer CA, Samuelsson B.; ''Reversible, calcium-dependent membrane association of human leukocyte 5-lipoxygenase.''; PubMed Europe PMC Scholia
  17. Yokomizo T, Ogawa Y, Uozumi N, Kume K, Izumi T, Shimizu T.; ''cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114826view16:32, 25 January 2021ReactomeTeamReactome version 75
113272view11:34, 2 November 2020ReactomeTeamReactome version 74
112484view15:44, 9 October 2020ReactomeTeamReactome version 73
101701view14:40, 1 November 2018DeSlOntology Term : 'lipoxygenase mediated pathway of arachidonic acid metabolism' added !
101396view11:28, 1 November 2018ReactomeTeamreactome version 66
100934view21:04, 31 October 2018ReactomeTeamreactome version 65
100722view20:11, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
15R-HETEMetaboliteCHEBI:63989 (ChEBI)
15S-HpETEMetaboliteCHEBI:15628 (ChEBI)
15epi-LXA4 MetaboliteCHEBI:63990 (ChEBI)
15epi-LXA4/B4ComplexR-ALL-2161609 (Reactome)
15epi-LXB4 MetaboliteCHEBI:63991 (ChEBI)
15k-LXA4MetaboliteCHEBI:63992 (ChEBI)
5S-HpETEMetaboliteCHEBI:15632 (ChEBI)
ALOX12 ProteinP18054 (Uniprot-TrEMBL)
ALOX12:Fe2+ComplexR-HSA-2142793 (Reactome)
ALOX5:ALOX5AP:LTC4SComplexR-HSA-2318764 (Reactome)
ALOX5AP ProteinP20292 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Fe2+ MetaboliteCHEBI:29033 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HPGD ProteinP15428 (Uniprot-TrEMBL)
HPGD dimerComplexR-HSA-2142778 (Reactome)
LTA4MetaboliteCHEBI:15651 (ChEBI)
LTC4S ProteinQ16873 (Uniprot-TrEMBL)
LXA4 MetaboliteCHEBI:6498 (ChEBI)
LXA4/B4ComplexR-ALL-2161856 (Reactome)
LXA4/B4ComplexR-ALL-9037644 (Reactome)
LXA4MetaboliteCHEBI:6498 (ChEBI)
LXB4 MetaboliteCHEBI:6499 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PTGR1ProteinQ14914 (Uniprot-TrEMBL)
dhk-LXA4MetaboliteCHEBI:63993 (ChEBI)
p-S272-ALOX5 ProteinP09917 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
15R-HETER-HSA-2161907 (Reactome)
15S-HpETER-HSA-2161917 (Reactome)
15epi-LXA4/B4ArrowR-HSA-2161907 (Reactome)
15k-LXA4ArrowR-HSA-2161779 (Reactome)
15k-LXA4R-HSA-2161844 (Reactome)
5S-HpETER-HSA-266051 (Reactome)
ALOX12:Fe2+mim-catalysisR-HSA-2161775 (Reactome)
ALOX5:ALOX5AP:LTC4Smim-catalysisR-HSA-2161907 (Reactome)
ALOX5:ALOX5AP:LTC4Smim-catalysisR-HSA-2161917 (Reactome)
ALOX5:ALOX5AP:LTC4Smim-catalysisR-HSA-266051 (Reactome)
H+ArrowR-HSA-2161779 (Reactome)
H+R-HSA-2161844 (Reactome)
H2OArrowR-HSA-266051 (Reactome)
HPGD dimermim-catalysisR-HSA-2161779 (Reactome)
LTA4ArrowR-HSA-266051 (Reactome)
LTA4ArrowR-HSA-9032036 (Reactome)
LTA4R-HSA-2161775 (Reactome)
LTA4R-HSA-9032036 (Reactome)
LXA4/B4ArrowR-HSA-2161775 (Reactome)
LXA4/B4ArrowR-HSA-2161917 (Reactome)
LXA4/B4ArrowR-HSA-9032054 (Reactome)
LXA4/B4R-HSA-9032054 (Reactome)
LXA4R-HSA-2161779 (Reactome)
NAD+R-HSA-2161779 (Reactome)
NADHArrowR-HSA-2161779 (Reactome)
NADP+ArrowR-HSA-2161844 (Reactome)
NADPHR-HSA-2161844 (Reactome)
O2R-HSA-2161775 (Reactome)
O2R-HSA-2161907 (Reactome)
O2R-HSA-2161917 (Reactome)
PTGR1mim-catalysisR-HSA-2161844 (Reactome)
R-HSA-2161775 (Reactome) Arachidonate 12-lipoxygenase, 12S-type (ALOX12) catalyses the conversion of leukotriene A4 (LTA4) into the lipoxins LXA4, which has its third hydroxyl positioned at C-6 and LXB4, which has it positioned at C-14 (Romano et al. 1993, Serhan & Sheppard 1990). One of the reaction intermediates of this process might be 5S,6S-epoxy-15S-hydroxy-7E,9E,11Z,13E-eicosatetraenoic acid (5,6-Ep-15S-HETE) (Puustinen et al. 1986). However, its generation from LTA4 is unclear but it can be hydrolysed to form the lipoxins.
R-HSA-2161779 (Reactome) 15-Hydroxyprostaglandin dehydrogenase (HPGD) converts lipoxin A4 (LXA4) to 15-oxo lipoxin A4 aka 15-keto-LXA4 (15k-LXA4) (Clish et al. 2000).
R-HSA-2161844 (Reactome) Prostaglandin reductase 1 (PTGR1) aka LTB4DH, a 15-oxoprostaglandin 13-reductase (Yokomizo et al. 1996), metabolises 15-oxo lipoxin A4 aka 15-keto-LXA4 (15k-LXA4) to produce 13,14-dihydro-15-keto-Lipoxin A4 (dhk-LXA4). This reaction has been inferred from a reaction in pig (Clish et al. 2000).
R-HSA-2161907 (Reactome) Arachidonate 5-lipoxygenase (ALOX5) converts 15R-hydro-eicosatetraenoic acid (15R-HETE) to the epi-lipoxins, 15epi-lipoxin A4 (15epi-LXA4) and 15epi-lipoxin B4 (15epi-LXB4) (Claria & Serhan 1995). These epi-lipoxins have altered configuration at the C-15 hydroxyl but similar biological potency.
R-HSA-2161917 (Reactome) Arachidonate 5-lipoxygenase (ALOX5) (Ueda et al. 1987) converts 15S-hydroperoxy-eicosatetraenoic acid (15S-HpETE) into lipoxin A4 (LXA4) and B4 (LXB4) (Serhan et al. 1984A, Serhan et al. 1984B). One of the reaction intermediates of this process might be 5S,6S-epoxy-15S-hydroxy-7E,9E,11Z,13E-eicosatetraenoic acid (5,6-Ep-15S-HETE) (Puustinen et al. 1986). However, its generation from LTA4 is unclear but it can be hydrolysed to form the lipoxins.
R-HSA-266051 (Reactome) In the second step of the formation of leukotriene A4 (LTA4) from arachidonic acid, arachidonate 5-lipoxygenase (ALOX5) converts 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) to an allylic epoxide, leukotriene A4 (LTA4) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986).
R-HSA-9032036 (Reactome) Leukotriene A4 (LTA4), produced by 5-lipoxygenase (ALOX5) in neutrophils, can be taken up by platelets where it is acted upon by 12-lipoxygenase (ALOX12) to form lipoxins (Samuelsson et al. 1987). The mechanism of translocation is unknown.
R-HSA-9032054 (Reactome) lipoxin A4 (LXA4) and B4 (LXB4) are released to the extracellular region by an unknown mechanism (Samuelsson et al. 1987).
dhk-LXA4ArrowR-HSA-2161844 (Reactome)
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