Leukotriene A-4 hydrolase

UniProt P09960 Organism Homo sapiens Gene LTA4, LTA4H EC 3.3.2.6, 3.4.11.4

Also known as: LTA4, LTA4H

Function

Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4). Can utilize LTA5 less effectively as a substrate than LTA4, and produce LTB5. Also has aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides. In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions.

Classification

Family (Pfam): PF09127 Leuk-A4-hydro_C, PF01433 Peptidase_M1, PF17900 Peptidase_M1_N
InterPro: Aminopeptidase_N-like_N, Aminopeptidase_N-like_N_sf, ARM-type_fold, LTA4H, LTA4H_cat, M1_LTA-4_hydro/amino_C_sf, M1_LTA4H, Peptidase_M1, Peptidase_M1_C, Peptidase_M1_dom, Peptidase_M4/M1_CTD_sf
Functional cluster: Oxidoreductases & Polyketide Synthases

Experimental structures · PDB · 77

1GW6 X-ray 2.20A
1H19 X-ray 2.10A
1HS6 X-ray 1.95A
1SQM X-ray 2.30A
2R59 X-ray 1.89A
2VJ8 X-ray 1.80A
3B7R X-ray 1.81A
3B7S X-ray 1.47A
3B7T X-ray 2.30A
3B7U X-ray 1.90A
3CHO X-ray 1.80A
3CHP X-ray 2.10A
… and 65 more

A predicted model is available from AlphaFold.

Gene Ontology · 21

Drugs targeting this protein · 1

ACEBILUSTAT inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Leukotriene A-4 hydrolase 2 shared papers
Prostaglandin G/H synthase 2 1 shared papers
Polyunsaturated fatty acid 5-lipoxygenase 1 shared papers

Literature · 33 cited papers

Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. Proc. Natl. Acad. Sci. U.S.A. · 2014
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. U.S.A. · 2012
Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features. Mol. Cell. Proteomics · 2012
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest. · 2011
A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science · 2010
Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J. Med. Chem. · 2009
Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science · 2009
Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem. Biol. · 2008
The full-ORF clone resource of the German cDNA consortium. BMC Genomics · 2007
The finished DNA sequence of human chromosome 12. Nature · 2006
… and 21 more in the literature graph

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