Leukotriene metabolic pathway (Homo sapiens)

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3111, 313, 29812, 14, 25, 307, 16, 2319197, 16, 236, 9, 10, 15, 18...2, 13, 285, 17, 19, 21, 24...41, 226, 15, 18, 20LegendMetaboliteProteinLTC4 synthasedeficiency2,4-dienoyl-CoA reductase (peroxisomal)12-Oxo-LTB4Arachidonate epoxygenase / epoxide hydrolaseGamma-glutamyl cycle16-COOH-tetranor-LTE3Eicosanoid metabolism via cytochrome P450 monooxygenases pathway20-hydroxy-LTE4LTA4HLTA4(C2)-COOH-LTELTC4LTE420-carboxy-LTE420-hydroxy-LTB4GlutathioneArachidonic acid16-carboxy-LTB4N-acetyl-LTE4LTD4PTGR120-COOH-LTB418-carboxy-LTE4GGT5ABCC1CYP4F35-LOAP5-LO20-oxo-LTB4(C2)-COOH-LTB5-HPETELTC4S5-LOleukotriene-E4 20-monooxygenase18-COOH-LTB4DPEP116-carboxy-LTE4LTB4GGT1GlutathionuriaCysteinylglycinase deficiency DPEP24LTC4DiseaseconversioncatalysisConnection to diseaseOther wikipathways2,4-dienoyl-CoA reductase (mitochondrial)14-COOH-hexanor-LTE4IschemicStrokeDeafness


Description

This pathway shows an overview of leukotrienes biosynthesis and metabolism. Leukotrienes are a group of biologically active lipid mediators who are derived pre-dominantly from arachidonic acid via the 5-lipoxygenase pathways. This pathway follow two routes, one include cysteinyl leukotrienes (LTC4, LTD4 and LTE4), the second starting at LTB4.

This pathway is linked to five disorders, out of which three are caused by hereditary primary defects in one enzyme also know as Inherited Metabolic Disorders or IMDs/IEMs (disorders depicted in pink). The clinical presentation of LTC4 synthase deficiency includes muscular hypotonia, psychomotor retardation, microcephaly and failure to thrive. The other two defects, gamma-glutamyl transpeptidase deficiency (GGT1 protein, also know as Glutathionuria) and membrane-bound dipeptidase deficiency (DPEP1 protein, responsible for a wide range of dipeptides hydrolytic reactions), have been studied to a lesser degree. Two additional disorders can be linked to this pathway: an increased risk of ischemic stroke is linked to the 5-LOAP protein (PMID:15640973 and 14770184) and deafness (ABCC1 autosomical dominant disorder, found in one family, severe hearing loss as adult, the relationship between the phenotype and gene is provisional).

This pathway was inspired by Chapter 38 of the book of Blau (ISBN 3642403360 (978-3642403361)).

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Bibliography

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  1. Wheelan P, Hankin JA, Bilir B, Guenette D, Murphy RC; ''Metabolic transformations of leukotriene B4 in primary cultures of human hepatocytes.''; J Pharmacol Exp Ther, 1999 PubMed Europe PMC Scholia
  2. Welsch DJ, Creely DP, Hauser SD, Mathis KJ, Krivi GG, Isakson PC; ''Molecular cloning and expression of human leukotriene-C4 synthase.''; Proc Natl Acad Sci U S A, 1994 PubMed Europe PMC Scholia
  3. Lam BK, Owen WF Jr, Austen KF, Soberman RJ; ''The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils.''; J Biol Chem, 1989 PubMed Europe PMC Scholia
  4. Wickham S, West MB, Cook PF, Hanigan MH; ''Gamma-glutamyl compounds: substrate specificity of gamma-glutamyl transpeptidase enzymes.''; Anal Biochem, 2011 PubMed Europe PMC Scholia
  5. Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M; ''Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver.''; FEBS Lett, 1994 PubMed Europe PMC Scholia
  6. De Carolis E, Denis D, Riendeau D; ''Oxidative inactivation of human 5-lipoxygenase in phosphatidylcholine vesicles.''; Eur J Biochem, 1996 PubMed Europe PMC Scholia
  7. Lee CW, Lewis RA, Corey EJ, Austen KF; ''Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes.''; Immunology, 1983 PubMed Europe PMC Scholia
  8. Mesa J, Alsina C, Oppermann U, Parés X, Farrés J, Porté S; ''Human prostaglandin reductase 1 (PGR1): Substrate specificity, inhibitor analysis and site-directed mutagenesis.''; Chem Biol Interact, 2015 PubMed Europe PMC Scholia
  9. Petrich K, Ludwig P, Kühn H, Schewe T; ''The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid: structure-activity relationship and mechanism of action.''; Biochem J, 1996 PubMed Europe PMC Scholia
  10. Ivanov I, Golovanov AB, Ferretti C, Canyelles-Niño M, Heydeck D, Stehling S, Lluch JM, González-Lafont À, Kühn H; ''Mutations of Triad Determinants Changes the Substrate Alignment at the Catalytic Center of Human ALOX5.''; ACS Chem Biol, 2019 PubMed Europe PMC Scholia
  11. Sala A, Voelkel N, Maclouf J, Murphy RC; ''Leukotriene E4 elimination and metabolism in normal human subjects.''; J Biol Chem, 1990 PubMed Europe PMC Scholia
  12. Odlander B, Claesson HE, Bergman T, Rådmark O, Jörnvall H, Haeggström JZ; ''Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji: indications of catalytically divergent forms of the enzyme.''; Arch Biochem Biophys, 1991 PubMed Europe PMC Scholia
  13. Gupta N, Gresser MJ, Ford-Hutchinson AW; ''Kinetic mechanism of glutathione conjugation to leukotriene A4 by leukotriene C4 synthase.''; Biochim Biophys Acta, 1998 PubMed Europe PMC Scholia
  14. Rudberg PC, Tholander F, Andberg M, Thunnissen MM, Haeggström JZ; ''Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
  15. Rouzer CA, Matsumoto T, Samuelsson B; ''Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities.''; Proc Natl Acad Sci U S A, 1986 PubMed Europe PMC Scholia
  16. Adachi H, Kubota I, Okamura N, Iwata H, Tsujimoto M, Nakazato H, Nishihara T, Noguchi T; ''Purification and characterization of human microsomal dipeptidase.''; J Biochem, 1989 PubMed Europe PMC Scholia
  17. Kalsotra A, Turman CM, Kikuta Y, Strobel HW; ''Expression and characterization of human cytochrome P450 4F11: Putative role in the metabolism of therapeutic drugs and eicosanoids.''; Toxicol Appl Pharmacol, 2004 PubMed Europe PMC Scholia
  18. Smyrniotis CJ, Barbour SR, Xia Z, Hixon MS, Holman TR; ''ATP allosterically activates the human 5-lipoxygenase molecular mechanism of arachidonic acid and 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid.''; Biochemistry, 2014 PubMed Europe PMC Scholia
  19. Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M; ''Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3).''; Arch Biochem Biophys, 1998 PubMed Europe PMC Scholia
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  22. Berry KA, Borgeat P, Gosselin J, Flamand L, Murphy RC; ''Urinary metabolites of leukotriene B4 in the human subject.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  23. Raulf M, König W, Köller M, Stüning M; ''Release and functional characterization of the leukotriene D4-metabolizing enzyme (dipeptidase) from human polymorphonuclear leucocytes.''; Scand J Immunol, 1987 PubMed Europe PMC Scholia
  24. Jin R, Koop DR, Raucy JL, Lasker JM; ''Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4.''; Arch Biochem Biophys, 1998 PubMed Europe PMC Scholia
  25. McGee J, Fitzpatrick F; ''Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes.''; J Biol Chem, 1985 PubMed Europe PMC Scholia
  26. Kikuta Y, Kato M, Yamashita Y, Miyauchi Y, Tanaka K, Kamada N, Kusunose M; ''Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization.''; DNA Cell Biol, 1998 PubMed Europe PMC Scholia
  27. Stec DE, Roman RJ, Flasch A, Rieder MJ; ''Functional polymorphism in human CYP4F2 decreases 20-HETE production.''; Physiol Genomics, 2007 PubMed Europe PMC Scholia
  28. Dalli J, Vlasakov I, Riley IR, Rodriguez AR, Spur BW, Petasis NA, Chiang N, Serhan CN; ''Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.''; Proc Natl Acad Sci U S A, 2016 PubMed Europe PMC Scholia
  29. Sjölinder M, Tornhamre S, Claesson HE, Hydman J, Lindgren J; ''Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1.''; J Lipid Res, 1999 PubMed Europe PMC Scholia
  30. Dalli J, Zhu M, Vlasenko NA, Deng B, Haeggström JZ, Petasis NA, Serhan CN; ''The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype.''; FASEB J, 2013 PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
125324view22:15, 31 January 2023LarsgwFix references
122629view10:53, 22 April 2022FehrhartUpdated layout for pathways
122590view10:21, 20 April 2022EweitzModified title
122520view12:55, 13 April 2022DeSlUpdated chapter nr in description
122499view08:17, 13 April 2022DeSlOntology Term : 'brain ischemia' added !
122498view08:16, 13 April 2022DeSlOntology Term : 'cerebrovascular disease' added !
122497view08:13, 13 April 2022DeSlAdded more details to description
122496view07:55, 13 April 2022DeSlUpdated description of PW
122495view07:50, 13 April 2022DeSlUpdated info for DPEP1 disorder; added link to other relevant PW
122494view07:42, 13 April 2022DeSlOntology Term : 'gamma-glutamyl transpeptidase deficiency' added !
122257view13:36, 16 March 2022PeterSwanenbergadded references
122173view21:26, 14 March 2022PeterSwanenbergOntology Term : 'cerebral infarction' added !
122172view21:24, 14 March 2022PeterSwanenbergOntology Term : 'autosomal dominant nonsyndromic deafness' added !
122171view21:18, 14 March 2022PeterSwanenbergtried making the RHEA and reactome IDs functional

some small layout changes

added 2 new diseases
122098view22:39, 10 March 2022DeSlConnected unconnected line
122097view22:27, 10 March 2022DeSlAdded comments on 16-carboxy-LTB4
122096view22:08, 10 March 2022DeSlAdded some more IDs for metabolites
122090view16:34, 10 March 2022DeSlAdded LTE3 metabolite node (no ID found yet)
122089view16:23, 10 March 2022DeSlAdded additonal ref for not annotated metabolites bottom right corner, added two protein annotations
122000view08:34, 9 March 2022PeterSwanenbergOntology Term : 'glutathionuria disease pathway' added !
121999view08:33, 9 March 2022PeterSwanenbergOntology Term : 'leukotriene C4 synthase deficiency pathway' added !
121650view11:17, 23 February 2022PeterSwanenbergLayout changes
121647view11:07, 23 February 2022PeterSwanenbergLayout changes
121642view10:05, 23 February 2022PeterSwanenbergAdded literature and some layout changes
121635view16:24, 22 February 2022PeterSwanenbergChanged one identifier
121599view18:10, 21 February 2022AndraOntology Term : 'leukotriene metabolic pathway' added !
121544view10:13, 21 February 2022PeterSwanenbergModified description
121540view10:10, 21 February 2022PeterSwanenbergAdded Legend
121534view09:07, 21 February 2022PeterSwanenbergForgot an arrow
121533view09:06, 21 February 2022PeterSwanenbergChange layout and addes some Pahtway nodes
121374view19:30, 16 February 2022PeterSwanenbergAdded enzymes and changed the layout
121344view18:15, 15 February 2022PeterSwanenbergCorrected the Rhea pathways

added extra found enzymes

applied OMIM numbers to disease
121188view22:06, 10 February 2022PeterSwanenbergAdded rhea pathways
121129view14:06, 9 February 2022PeterSwanenberg
121120view10:13, 9 February 2022PeterSwanenberg
121119view10:00, 9 February 2022PeterSwanenbergNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(C2)-COOH-LTBMetabolite
(C2)-COOH-LTEMetabolite
12-Oxo-LTB4MetaboliteCHEBI:27814 (ChEBI) Found in reactome reaction: arachidonic acid metabolism
14-COOH-hexanor-LTE4MetaboliteCHEBI:74019 (ChEBI) Structure from PMID:17623009 is exact match with CHEBI:74019, aka 14-carboxy-15,16,17,18,19,20-hexanor-leukotriene E3
16-COOH-tetranor-LTE3MetaboliteCHEBI:74014 (ChEBI) Structure from PMID:17623009 is exact match with CHEBI:74014, aka 16-carboxy-17,18,19,20-tetranor-leukotriene E3
16-carboxy-LTB4MetaboliteAccording to Fig.8 from PMID:21526749, might also be called 16-COOH-tetranor-LTB3
16-carboxy-LTE4MetaboliteCould potentially be CHEBI:74016
18-COOH-LTB4MetaboliteCHEBI:63980 (ChEBI)
  • Found in reactome reaction: arachidonic acid metabolism
  • Full name: 18-hydroxy-18-oxo-dinorleukotriene B4
18-carboxy-LTE4MetaboliteCHEBI:74017 (ChEBI) aka 18-COOH-LTE4,PMID: 2174886. Structural depiction in PMID:2174886 is exact match with 18-carboxy-19,20-dinor-leukotriene E4 (CHEBI:74017)
2,4-dienoyl-CoA reductase (mitochondrial)ProteinQ16698 (Uniprot-TrEMBL) PMID: 2174886; localization info not provided
2,4-dienoyl-CoA reductase (peroxisomal)ProteinQ9NUI1 (Uniprot-TrEMBL) PMID: 2174886; localization info not provided
20-COOH-LTB4MetaboliteCHEBI:27562 (ChEBI)
  • CHEBI id lead to20-hydroxy-20-oxoleukotriene but according to Rhea is the same as 20-carboxy-LTB4
  • has both CHEBI: 27562 and 90722 who are very similair and only differ in charge. no charge mentioned in Blau therefero 27562 is chosen
20-carboxy-LTE4MetaboliteCHEBI:134517 (ChEBI) PMID: 2174886
20-hydroxy-LTB4MetaboliteCHEBI:15646 (ChEBI)
20-hydroxy-LTE4MetaboliteCHEBI:28700 (ChEBI)
20-oxo-LTB4MetaboliteCHEBI:63979 (ChEBI)
  • looks firs like a conversion from hydroxy to oxo (RHEA:48668) and then from oxo to carboxy (RHEA:48672)
  • found by RHE reactions described above
5-HPETEMetaboliteCHEBI:15632 (ChEBI) 5-HPETE: 5-Hydroperoxyeicosatetraenoic acid
5-LOAPGeneProductENSG00000132965 (Ensembl) 5-LOAP: 5-lipoxygenase-activating protein found as ALOX5AP
5-LOGeneProductENSG00000012779 (Ensembl)
  • 5-LO: 5-lipoxygenase
  • Found as gene ALOX5
ABCC1GeneProductENSG00000103222 (Ensembl) Found in reactome reaction: arachidonic acid metabolism
Arachidonate epoxygenase / epoxide hydrolasePathwayWP678 (WikiPathways)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
CYP4F3GeneProductENSG00000186529 (Ensembl) CYP4F3 or LTB4H
DPEP1GeneProductENSG00000015413 (Ensembl) DPEP1: membrane-bound dipeptidase
DPEP2GeneProductENSG00000167261 (Ensembl)
  • Full name: Dipeptidase 1
  • Found in RHEA reaction with uniprot
Eicosanoid metabolism via cytochrome P450 monooxygenases pathwayPathwayWP4720 (WikiPathways)
GGT1GeneProductENSG00000100031 (Ensembl) GGT1: Gamma-glutamyl transpeptidase
GGT5GeneProductENSG00000099998 (Ensembl)
  • GGT5 or GGTLA1
  • Founde by rhea reaction and than the uniprot search
Gamma-glutamyl cyclePathwayWP4518 (WikiPathways)
GlutathioneMetaboliteCHEBI:16856 (ChEBI)
LTA4MetaboliteCHEBI:15651 (ChEBI)
LTA4HGeneProductENSG00000111144 (Ensembl)
LTB4MetaboliteCHEBI:15647 (ChEBI)
LTC4MetaboliteCHEBI:16978 (ChEBI)
LTC4SGeneProductENSG00000213316 (Ensembl) LTC4S: LTC4 synthase
LTD4MetaboliteCHEBI:28666 (ChEBI)
LTE4MetaboliteCHEBI:15650 (ChEBI) PMID: 2174886
N-acetyl-LTE4MetaboliteCHEBI:7210 (ChEBI) PMID: 2174886
PTGR1GeneProductENSG00000106853 (Ensembl) Found in reactome reaction: arachidonic acid metabolism
leukotriene-E4 20-monooxygenaseGeneProduct1.14.13.34 (Enzyme Nomenclature)
  • Found on Rhea in the cross-references section in MetaCyc that leukotriene-E4 20-monooxygenase is involved in this reaction

    https://biocyc.org/META/NEW-IMAGE?type=REACTION&object=LEUKOTRIENE-E4-20-MONOOXYGENASE-RXN

  • BRENDA site: https://www.brenda-enzymes.org/enzyme.php?ecno=1.14.13.34#SYSTEMATIC%20NAME
  • PMID: 2174886 N-acyetyl transferase

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
20-COOH-LTB418-COOH-LTB4mim-conversionR-HSA-2161790.2 (Reactome) found in reactome pathway: arachidonic acid metabolism
20-hydroxy-LTB420-oxo-LTB4mim-conversion48669 (Rhea)
20-oxo-LTB420-COOH-LTB4mim-conversion48673 (Rhea) looks firs like a conversion from hydroxy to oxo (RHEA:48668) and then from oxo to carboxy (RHEA:48672)
5-HPETELTA4mim-conversion17962 (Rhea)
Arachidonic acid5-HPETEmim-conversion17486 (Rhea)
LTA4LTB4mim-conversion22325 (Rhea)
LTA4LTC4mim-conversion17619 (Rhea)
LTB412-Oxo-LTB4mim-conversion50609 (Rhea) Found in reactome reaction: arachidonic acid metabolism
LTB420-hydroxy-LTB4mim-conversion22177 (Rhea)
LTC4LTC4ArrowR-HSA-266070.1 (Reactome) Transport activity of ABCC1
LTC4LTD4mim-conversion31564 (Rhea)
LTD4LTE4mim-conversion48616 (Rhea)
  • DPEP1 is in the undefined reaction direction in RHEA:48616, but not from left-to-right
  • Reactome Id does say conversion to LTE4 ID:R-HSA-266012.3
LTD4LTE4mim-conversion48617 (Rhea)
LTE420-hydroxy-LTE4mim-conversion24121 (Rhea) No human literature, only found in rats
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5171"
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