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Literature summary extracted from

  • Snelgrove, R.; Kheradmand, F.
    Leukotriene A4 hydrolase the Janus enzyme shows its ugly side in smokers (2014), Am. J. Respir. Crit. Care Med., 190, 5-7 .
    View publication on PubMedView publication on EuropePMC

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.3.2.6 acrolein acrolein in cigarette smoke in part inhibits LTA4H peptidase activity Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.3.2.6 extracellular
-
 Homo sapiens
-
-
3.3.2.6 intracellular
-
 Homo sapiens 5622
-

Organism

EC Number Organism UniProt Comment Textmining
3.3.2.6 Homo sapiens P09960
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.3.2.6 neutrophil
-
 Homo sapiens
-

Synonyms

EC Number Synonyms Comment Organism
3.3.2.6 leukotriene A4 hydrolase
-
 Homo sapiens
3.3.2.6 LT A4 hydrolase
-
 Homo sapiens
3.3.2.6 LTA4H
-
 Homo sapiens

General Information

EC Number General Information Comment Organism
3.3.2.6 physiological function ELR1 CXC chemokines (e.g. interleukin-8) bind to CXCR1 and CXCR2 receptors expressed on neutrophils, and attract them to sites of inflammation. Ensuing degradation of collagen by neutrophil-derived proteases generates many tripeptide proline-glycine-proline (PGP) peptides that mimic key sequences found in ELR1 CXC chemokines, and act as a potent neutrophil chemoattractant. Extracellular leukotriene (LT) A4 hydrolase (LTA4H) degrades PGP and resolves neutrophilic inflammation, whereas intracellular epoxide hydrolase function (EC 3.3.2.10) of the same enzyme converts LTA4 to LTB4. LTB4 is a proinflammatory lipid mediator capable of recruiting and activating an array of cells, including neutrophils. The intracellular activity of LTA4H within leukocytes can generate the lipid mediator LTB4 that can also promote neutrophil recruitment by binding to LTB4 receptor (BLT1).Thus, LTA4H exhibits opposing pro- and anti-inflammatory roles that govern neutrophil recruitment. Cigarette smoke disrupts leukotriene (LT) A4 hydrolase (LTA4H)-mediated resolution of pulmonary neutrophilic inflammation. In response to infection or injury, resident cells within the lung will release chemoattractants that will promote neutrophil recruitment from the vasculature and into the tissue. Epithelial cells and alveolar macrophages, for example, may release IL-8 that will bind to CXCR1/2 on the surface of the neutrophil and promote recruitment. Cigarette smoke chemically acetylates PGP, enhancing its chemotactic activity and protecting it from degradation by LTA4H. Second, biochemical and preliminary murine studies suggest that cigarette smoke can selectively abrogate the peptidase activity of LTA4H, with minimal effect on the hydrolase activity. Thus, cigarette smoke pushes LTA4H toward a uniquely proinflammatory phenotype, whereby LTB4 and PGP together induce increased pulmonary neutrophilic inflammation. Acrolein in cigarette smoke in part inhibits LTA4H peptidase activity. Acrolein, derived from cigarette smoke or physiologically during inflammation (lipid peroxidation, metabolism of threonine or spermine), can inhibit LTA4H-mediated degradation of PGP, allowing the peptide to accumulate and maintain neutrophilic inflammation. LTA4H enzyme inhibitors may fail to distinguish between the opposing activities of the enzyme, and could inadvertently lead to persistent neutrophilia Homo sapiens