Leukotriene metabolic pathway (WP5171)

Homo sapiens

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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)).

Authors

Peter Swanenberg , Andra Waagmeester , Denise Slenter , Eric Weitz , Friederike Ehrhart , and Lars Willighagen

Activity

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology

cerebral infarction autosomal dominant nonsyndromic deafness cerebrovascular disease gamma-glutamyl transpeptidase deficiency brain ischemia

Pathway Ontology

leukotriene metabolic pathway leukotriene C4 synthase deficiency pathway glutathionuria disease pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
12-Oxo-LTB4 Metabolite chebi:27814 Found in reactome reaction: arachidonic acid metabolism
16-COOH-tetranor-LTE3 Metabolite chebi:74014 Structure from PMID:17623009 is exact match with CHEBI:74014, aka 16-carboxy-17,18,19,20-tetranor-leukotriene E3
20-hydroxy-LTE4 Metabolite chebi:28700
LTA4 Metabolite chebi:15651
LTC4 Metabolite chebi:16978
LTE4 Metabolite chebi:15650 PMID: 2174886
20-carboxy-LTE4 Metabolite chebi:134517 PMID: 2174886
20-hydroxy-LTB4 Metabolite chebi:15646
Glutathione Metabolite chebi:16856
Arachidonic acid Metabolite chebi:15843
N-acetyl-LTE4 Metabolite chebi:7210 PMID: 2174886
LTD4 Metabolite chebi:28666
20-COOH-LTB4 Metabolite chebi:27562 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
18-carboxy-LTE4 Metabolite chebi:74017 aka 18-COOH-LTE4,PMID: 2174886. Structural depiction in PMID:2174886 is exact match with 18-carboxy-19,20-dinor-leukotriene E4 (CHEBI:74017)
20-oxo-LTB4 Metabolite chebi:63979 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-HPETE Metabolite chebi:15632 5-HPETE: 5-Hydroperoxyeicosatetraenoic acid
18-COOH-LTB4 Metabolite chebi:63980 Found in reactome reaction: arachidonic acid metabolism
Full name: 18-hydroxy-18-oxo-dinorleukotriene B4
LTB4 Metabolite chebi:15647
14-COOH-hexanor-LTE4 Metabolite chebi:74019 Structure from PMID:17623009 is exact match with CHEBI:74019, aka 14-carboxy-15,16,17,18,19,20-hexanor-leukotriene E3
LTA4H GeneProduct ensembl:ENSG00000111144
PTGR1 GeneProduct ensembl:ENSG00000106853 Found in reactome reaction: arachidonic acid metabolism
GGT5 GeneProduct ensembl:ENSG00000099998 GGT5 or GGTLA1
Founde by rhea reaction and than the uniprot search
ABCC1 GeneProduct ensembl:ENSG00000103222 Found in reactome reaction: arachidonic acid metabolism
CYP4F3 GeneProduct ensembl:ENSG00000186529 CYP4F3 or LTB4H
5-LOAP GeneProduct ensembl:ENSG00000132965 5-LOAP: 5-lipoxygenase-activating protein found as ALOX5AP
5-LO GeneProduct ensembl:ENSG00000012779 5-LO: 5-LO 5-lipoxygenase
Found as gene ALOX5
LTC4S GeneProduct ensembl:ENSG00000213316 LTC4S: LTC4 synthase
5-LO GeneProduct ensembl:ENSG00000012779 5-LO: 5-lipoxygenase
Found as gene ALOX5
leukotriene-E4 20-monooxygenase GeneProduct eccode:1.14.13.34 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
DPEP1 GeneProduct ensembl:ENSG00000015413 DPEP1: membrane-bound dipeptidase
GGT1 GeneProduct ensembl:ENSG00000100031 GGT1: Gamma-glutamyl transpeptidase
DPEP2 GeneProduct ensembl:ENSG00000167261 Full name: Dipeptidase 1
Found in RHEA reaction with uniprot
2,4-dienoyl-CoA reductase (peroxisomal) Protein uniprot:Q9NUI1 PMID: 2174886; localization info not provided
2,4-dienoyl-CoA reductase (mitochondrial) Protein uniprot:Q16698 PMID: 2174886; localization info not provided

References

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