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Leukotriene A4 hydrolase

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1395

Nomenclature: Leukotriene A4 hydrolase

Family: Leukotriene and lipoxin metabolism, M1: Aminopeptidase N, Hydrolases & Lipases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 611 12q23.1 LTA4H leukotriene A4 hydrolase
Mouse - 611 10 C2 Lta4h leukotriene A4 hydrolase
Rat - 610 7q13 Lta4h leukotriene A4 hydrolase
Database Links Click here for help
Specialist databases
MEROPS M01.004 (Hs)
Other databases
Alphafold P09960 (Hs), P24527 (Mm), P30349 (Rn)
BRENDA 3.3.2.6
ChEMBL Target CHEMBL4618 (Hs), CHEMBL3738 (Mm), CHEMBL2400 (Rn)
Ensembl Gene ENSG00000111144 (Hs), ENSMUSG00000015889 (Mm), ENSRNOG00000004494 (Rn)
Entrez Gene 4048 (Hs), 16993 (Mm), 299732 (Rn)
Human Protein Atlas ENSG00000111144 (Hs)
KEGG Enzyme 3.3.2.6
KEGG Gene hsa:4048 (Hs), mmu:16993 (Mm), rno:299732 (Rn)
OMIM 151570 (Hs)
Pharos P09960 (Hs)
RefSeq Nucleotide NM_001256643 (Hs), NM_001256644 (Hs), NM_000895 (Hs), NM_008517 (Mm), NM_001030031 (Rn)
RefSeq Protein NP_000886 (Hs), NP_001243573 (Hs), NP_001243572 (Hs), NP_032543 (Mm), NP_001025202 (Rn)
SynPHARM 13735 (in complex with bestatin)
83483 (in complex with compound 1a [PMID: 25692029])
78669 (in complex with DG-051)
UniProtKB P09960 (Hs), P24527 (Mm), P30349 (Rn)
Wikipedia LTA4H (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human LTA4H mutant E271A in complex with LTA4 (crystal form I).
PDB Id:  5NI2
Ligand:  LTA4
Resolution:  1.5Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 3.3.2.6

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
4-OMe-ARM1 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Activation - - 4
⤷ AC50= 83 nM [4]
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 1a [PMID: 25692029] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pKi 2,12
⤷ pKi 8.3 (Ki 5.4x10-9 M) [2,12]
kelatorphan Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pKi 7
⤷ pKi 8.0 (Ki 1x10-8 M) [7]
bestatin Small molecule or natural product Hs Inhibition 5.4 pKi 6
⤷ pKi 5.4 (Ki 4x10-6 M) [6]
Description: Inhibition of LTB4 formation by isolated human enzyme in vitro.
LYS006 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.4 – 8.7 pIC50 1,5
⤷ pIC50 8.7 (IC50 2x10-9 M) [1]
Description: Inhibition of enzyme activity determined in a fluorescence assay using a 7-amino-4-methylcoumarin (AMC) arginine derivative (Arg-AMC) as a surrogate substrate for LTA4H.
pIC50 8.4 (IC50 3.7x10-9 M) [5]
Description: Determined in human PBMC
DG-051 Small molecule or natural product Hs Inhibition 7.3 pIC50 9
⤷ pIC50 7.3 (IC50 4.7x10-8 M) [9]
acebilustat Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.2 – 7.2 pIC50 10
⤷ pIC50 7.2 – 7.2 (IC50 6.8x10-8 – 6x10-8 M) [10]
Description: Inhibition of LTA4H activity by the inhibitor is measured as reduction in LTB4 production in human whole blood, by ELISA
SC-22716 Small molecule or natural product Hs Inhibition 6.7 pIC50 8
⤷ pIC50 6.7 (IC50 2x10-7 M) [8]
Immunopharmacology Comments
LTA4H is an established immunomodulatory target. LTA4H exhibits opposing pro- and anti-inflammatory functions: epoxide hydrolase (EH) activity which catalyses the hydrolysis of leukotriene A4 to leukotriene B4, which promotes neutrophilic inflammation, and aminopeptidase (AP) activity which catalyses the hydrolysis of the tripeptide proline-glycine-proline (PGP) to promote resolution of neutrophilic infiltration.

Expression has been identified in some cancer cells, where it may play a role in the development and progression of cancers associated with chronic inflammation, suggesting that LTA4H inhibitors may have efficacy as anti-cancer therapeutics [3]. X-ray structures revealing the dynamic domain movements taking place upon substrate (LTA4) interaction will allow for more rational drug design [11].

On the other hand, activators of LTA4H AP activity have potential to enhance the anti-inflammatory properties of the enzyme [4].

References

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1. Bollbuck B, Merkert C, Miltz W, Roehn T. (2015) Heteroaryl butanoic acid derivatives as lta4h inhibitors. Patent number: WO2015092740A1. Assignee: Novartis Ag. Priority date: 20/12/2013. Publication date: 25/06/2015.

2. Bonnard E, Poras H, Nadal X, Maldonado R, Fournié-Zaluski MC, Roques BP. (2015) Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. Pharmacol Res Perspect, 3 (2): e00116. [PMID:25692029]

3. Chen X, Wang S, Wu N, Yang CS. (2004) Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Curr Cancer Drug Targets, 4 (3): 267-83. [PMID:15134534]

4. Lee KH, Petruncio G, Shim A, Burdick M, Zhang Z, Shim YM, Noble SM, Paige M. (2019) Effect of Modifier Structure on the Activation of Leukotriene A4 Hydrolase Aminopeptidase Activity. J Med Chem, 62 (23): 10605-10616. [PMID:31751136]

5. Markert C, Thoma G, Srinivas H, Bollbuck B, Lüönd RM, Miltz W, Wälchli R, Wolf R, Hinrichs J, Bergsdorf C et al.. (2021) Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase. J Med Chem, 64 (4): 1889-1903. [PMID:33592148]

6. Orning L, Krivi G, Fitzpatrick FA. (1991) Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J Biol Chem, 266 (3): 1375-8. [PMID:1846352]

7. Penning TD, Askonas LJ, Djuric SW, Haack RA, Yu SS, Michener ML, Krivi GG, Pyla E. (1995) Kelatorphan and related analogs: potent and selective inhibitors of leukotriene A4 hydrolase. Bioorganic and Medicinal Chemistry Letters, 5: 2517-2522. DOI: 10.1016/0960-894X(95)00441-U

8. Penning TD, Chandrakumar NS, Chen BB, Chen HY, Desai BN, Djuric SW, Docter SH, Gasiecki AF, Haack RA, Miyashiro JM et al.. (2000) Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. J Med Chem, 43 (4): 721-35. [PMID:10691697]

9. Sandanayaka V, Mamat B, Mishra RK, Winger J, Krohn M, Zhou LM, Keyvan M, Enache L, Sullins D, Onua E et al.. (2010) Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. J Med Chem, 53 (2): 573-85. [PMID:19950900]

10. Springman EB, Pugh MM, Bhatt L, Grosswald R. (2014) Methods of inhibiting leukotriene a4 hydrolase. Patent number: WO2014164658A1. Assignee: Celtaxsys, Inc.. Priority date: 13/03/2013. Publication date: 09/10/2014.

11. Stsiapanava A, Samuelsson B, Haeggström JZ. (2017) Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis. Proc Natl Acad Sci USA, 114 (36): 9689-9694. [PMID:28827365]

12. Tholander F, Muroya A, Roques BP, Fournié-Zaluski MC, Thunnissen MM, Haeggström JZ. (2008) Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol, 15 (9): 920-9. [PMID:18804029]

Contributors

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