Leukotriene A4 hydrolase

Target id: 1395

Nomenclature: Leukotriene A4 hydrolase

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

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     Leukotriene A4 hydrolase has curated GtoImmuPdb data

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
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
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:  6
Enzyme Reaction
EC Number: 3.3.2.6

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

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 1a [PMID: 25692029] Hs Inhibition 8.3 pKi 1,7
pKi 8.3 (Ki 5.4x10-9 M) [1,7]
DG-051 Hs Inhibition 7.3 pIC50 5
pIC50 7.3 (IC50 4.7x10-8 M) [5]
SC-22716 Hs Inhibition 6.7 pIC50 4
pIC50 6.7 (IC50 2x10-7 M) [4]
bestatin Hs Inhibition - - 3
[3]
Immunopharmacology Comments
LTA4H is an established anti-inflammatory target. 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 [2]. X-ray structures revealing the dynamic domain movements taking place upon substrate (LTA4) interaction will allow for more rational drug design [6].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  neutrophil degranulation (GO:0043312) TAS
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  neutrophil degranulation (GO:0043312) TAS
References: 

References

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1. 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 Perspect3 (2): e00116. [PMID:25692029]

2. Chen X, Wang S, Wu N, Yang CS. (2004) Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Curr Cancer Drug Targets4 (3): 267-83. [PMID:15134534]

3. 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]

4. 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]

5. 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]

6. 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.,  [Epub ahead of print]. [PMID:28827365]

7. 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]

How to cite this page

Leukotriene and lipoxin metabolism: Leukotriene A4 hydrolase. Last modified on 23/08/2017. Accessed on 18/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1395.