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5-LOX

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Target id: 1385

Nomenclature: 5-LOX

Family: Lipoxygenases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 674 10q11.21 ALOX5 arachidonate 5-lipoxygenase
Mouse - 674 6 53.79 cM Alox5 arachidonate 5-lipoxygenase
Rat - 673 4q42 Alox5 arachidonate 5-lipoxygenase
Previous and Unofficial Names Click here for help
ALOX5 | 5-lipoxygenase | 5-LO | arachidonate 5-lipoxygenase
Database Links Click here for help
Alphafold P09917 (Hs), P48999 (Mm), P12527 (Rn)
BRENDA 1.13.11.34
CATH/Gene3D 2.60.60.20
ChEMBL Target CHEMBL215 (Hs), CHEMBL5211 (Mm), CHEMBL312 (Rn)
DrugBank Target P09917 (Hs)
Ensembl Gene ENSG00000012779 (Hs), ENSMUSG00000025701 (Mm), ENSRNOG00000012972 (Rn)
Entrez Gene 240 (Hs), 11689 (Mm), 25290 (Rn)
Human Protein Atlas ENSG00000012779 (Hs)
KEGG Enzyme 1.13.11.34
KEGG Gene hsa:240 (Hs), mmu:11689 (Mm), rno:25290 (Rn)
OMIM 152390 (Hs)
Pharos P09917 (Hs)
UniProtKB P09917 (Hs), P48999 (Mm), P12527 (Rn)
Wikipedia ALOX5 (Hs)
Enzyme Reaction Click here for help
EC Number: 1.13.11.34 Arachidonic acid + O2 = LTA4 + H2O
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
arachidonic acid Substrate is endogenous in the given species Hs - -
Endogenous inhibitor
Protein kinase A-mediated phosphorylation  [9]

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Activators
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
5-LOX activating protein {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Activation - -
⤷
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CJ13610 Small molecule or natural product Hs Inhibition 7.2 pIC50 6
⤷ pIC50 7.2 (IC50 7x10-8 M) [6]
2-TEDC Small molecule or natural product Rn Inhibition 7.1 pIC50 4
⤷ pIC50 7.1 (IC50 9x10-8 M) [4]
Description: Inhibitory activity against 5-LOX in rat polymorphonuclear leukocytes
BW B70C Small molecule or natural product Hs Inhibition 6.7 pIC50 13
⤷ pIC50 6.7 [13]
PF-04191834 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 6.6 pIC50 10
⤷ pIC50 6.6 (IC50 2.29x10-7 M) [10]
zileuton Small molecule or natural product Approved drug Primary target of this compound Immunopharmacology Ligand Hs Inhibition 5.8 – 6.5 pIC50 2,14,17
⤷ pIC50 6.5 (IC50 3x10-7 M) [14]
Description: Inhibition of recombinant 5-LOX in vitro.
pIC50 6.4 (IC50 4x10-7 M) [2]
Description: Inhibition of leukotriene B4 biosynthesis by human polymorphonuclear leukocytes.
pIC50 5.8 (IC50 1.5x10-6 M) [17]
Description: Inhibition of purified recombinant human 5-LOX in a cell-free assay.
5-LOX inhibitor 2m [PMID: 30199704] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.1 pIC50 17
⤷ pIC50 6.1 (IC50 9x10-7 M) [17]
Description: In vitro biochemical inhibitory activity.
Honokiol Small molecule or natural product Ligand has a PDB structure Hs Inhibition 5.4 pIC50 15
⤷ pIC50 5.4 (IC50 4.2x10-6 M) [15]
Description: Inhibition of 5LOX-mediated LTB4 formation in stimulated human polymorphonuclear leukocytes.
View species-specific inhibitor tables
Immunopharmacology Comments
5-LOX is included in GtoImmuPdb because of its involvement in eicosanoid turnover and because it is being actively pursued as a molecular target for the development of novel anti-inflammatory therapeutics [17]. 5-LOX inhibitors with dual activity at other targets within the arachadonic acid/eicosanoid metabolic pathway (e.g. COX1/2, soluble epoxide hydrolase, mPGES1) are also being designed as more effective anti-inflammatory agents [1,3,5,7-8,11-12,16].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Asthma, susceptibility to
Disease Ontology: DOID:2841
OMIM: 600807
Role:  Mutations in ALOX5 are associated with diminished response to antileukotriene treatment in asthma.

References

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1. Abdelgawad MA, Labib MB, Ali WAM, Kamel G, Azouz AA, El-Nahass ES. (2018) Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies. Bioorg Chem, 78: 103-114. [PMID:29550530]

2. Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, Summers JB, Brooks DW. (1991) 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther, 256 (3): 929-37. [PMID:1848634]

3. Chaaban I, Rizk OH, Ibrahim TM, Henen SS, El-Khawass EM, Bayad AE, El-Ashmawy IM, Nematalla HA. (2018) Synthesis, anti-inflammatory screening, molecular docking, and COX-1,2/-5-LOX inhibition profile of some novel quinoline derivatives. Bioorg Chem, 78: 220-235. [PMID:29602046]

4. Cho H, Ueda M, Tamaoka M, Hamaguchi M, Aisaka K, Kiso Y, Inoue T, Ogino R, Tatsuoka T, Ishihara T et al.. (1991) Novel caffeic acid derivatives: extremely potent inhibitors of 12-lipoxygenase. J Med Chem, 34 (4): 1503-5. [PMID:2016727]

5. El-Nagar MKS, Abdu-Allah HHM, Salem OIA, Kafafy AN, Farghaly HSM. (2018) Novel N-substituted 5-aminosalicylamides as dual inhibitors of cyclooxygenase and 5-lipoxygenase enzymes: Synthesis, biological evaluation and docking study. Bioorg Chem, 78: 80-93. [PMID:29550533]

6. Fischer L, Steinhilber D, Werz O. (2004) Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor CJ-13,610. Br J Pharmacol, 142 (5): 861-8. [PMID:15197110]

7. Garscha U, Romp E, Pace S, Rossi A, Temml V, Schuster D, König S, Gerstmeier J, Liening S, Werner M et al.. (2017) Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase. Sci Rep, 7 (1): 9398. [PMID:28839250]

8. Liu Y, Duan C, Chen H, Wang C, Liu X, Qiu M, Tang H, Zhang F, Zhou X, Yang J. (2018) Inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate crystal-induced inflammation. Toxicol Appl Pharmacol, 351: 1-11. [PMID:29763636]

9. Luo M, Jones SM, Phare SM, Coffey MJ, Peters-Golden M, Brock TG. (2004) Protein kinase A inhibits leukotriene synthesis by phosphorylation of 5-lipoxygenase on serine 523. J Biol Chem, 279 (40): 41512-20. [PMID:15280375]

10. Masferrer JL, Zweifel BS, Hardy M, Anderson GD, Dufield D, Cortes-Burgos L, Pufahl RA, Graneto M. (2010) Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. J Pharmacol Exp Ther, 334 (1): 294-301. [PMID:20378715]

11. Nandha B, Ramareddy SA, Kuntal H. (2018) Synthesis of substituted fluorobenzimidazoles as inhibitors of 5-lipoxygenase and soluble epoxide hydrolase for anti-inflammatory activity. Arch Pharm (Weinheim), 351 (6): e1800030. [PMID:29732612]

12. P JJ, Manju SL, Ethiraj KR, Elias G. (2018) Safer anti-inflammatory therapy through dual COX-2/5-LOX inhibitors: A structure-based approach. Eur J Pharm Sci, 121: 356-381. [PMID:29883727]

13. Payne AN, Jackson WP, Salmon JA, Nicholls A, Yeadon M, Garland LG. (1991) Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma. Agents Actions Suppl, 34: 189-99. [PMID:1793063]

14. Prasher P, Pooja, Singh P. (2014) Lead modification: amino acid appended indoles as highly effective 5-LOX inhibitors. Bioorg Med Chem, 22 (5): 1642-8. [PMID:24508141]

15. Schühly W, Hüfner A, Pferschy-Wenzig EM, Prettner E, Adams M, Bodensieck A, Kunert O, Oluwemimo A, Haslinger E, Bauer R. (2009) Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation. Bioorg Med Chem, 17 (13): 4459-65. [PMID:19481465]

16. Singh P, Prasher P, Dhillon P, Bhatti R. (2015) Indole based peptidomimetics as anti-inflammatory and anti-hyperalgesic agents: Dual inhibition of 5-LOX and COX-2 enzymes. Eur J Med Chem, 97: 104-23. [PMID:25956953]

17. Sinha S, Doble M, Manju SL. (2018) Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase. Eur J Med Chem, 158: 34-50. [PMID:30199704]

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