Leukotriene A<sub>4</sub> hydrolase | Leukotriene and lipoxin metabolism | IUPHAR/BPS Guide to PHARMACOLOGY

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Leukotriene A4 hydrolase

target has curated data in GtoImmuPdb

Target id: 1395

Nomenclature: Leukotriene A4 hydrolase

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

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 611 12q22 LTA4H leukotriene A4 hydrolase
Mouse - 611 10 C3 Lta4h leukotriene A4 hydrolase
Rat - 611 7q13 Lta4h leukotriene A4 hydrolase
Database Links
Specialist databases
MEROPS M01.004 (Hs)
Other databases
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_000895 (Hs), NM_001256644 (Hs), NM_001256643 (Hs), NM_008517 (Mm), NM_001030031 (Rn)
RefSeq Protein NP_001243573 (Hs), NP_001243572 (Hs), NP_000886 (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
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:  8
Enzyme Reaction
EC Number: 3.3.2.6

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
4-OMe-ARM1 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] Hs Inhibition 8.3 pKi 2,9
⤷ pKi 8.3 (Ki 5.4x10-9 M) [2,9]
bestatin Hs Inhibition 5.4 pKi 5
⤷ pKi 5.4 (Ki 4x10-6 M) [5]
Description: Inhibition of LTB4 formation by isolated human enzyme in vitro.
LYS006 Hs Inhibition 8.7 pIC50 1
⤷ 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.
DG-051 Hs Inhibition 7.3 pIC50 7
⤷ pIC50 7.3 (IC50 4.7x10-8 M) [7]
SC-22716 Hs Inhibition 6.7 pIC50 6
⤷ pIC50 6.7 (IC50 2x10-7 M) [6]
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 [8].

On the other hand, activators of LTA4H AP activity have potential to enhance the anti-inflammatory properties of the enzyme [4].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS

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. 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]

6. 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]

7. 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]

8. 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. U.S.A., 114 (36): 9689-9694. [PMID:28827365]

9. 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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