8AWH

Leukotriene A4 hydrolase in complex with 4-(4-Benzylphenyl)-selenazol-2-amine

Summary for 8AWH

• Entry DOI: 10.2210/pdb8awh/pdb
• Related: 4L2L
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, YTTERBIUM (III) ION, ... (8 entities in total)
• Functional Keywords: leukotriene b4, complex, inhibitor, inflammation, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 71649.17

Authors

Teder, T.,Haeggstrom, J.Z. (deposition date: 2022-08-29, release date: 2023-05-03, Last modification date: 2024-02-07)

Primary citation

Teder, T.,Konig, S.,Singh, R.,Samuelsson, B.,Werz, O.,Garscha, U.,Haeggstrom, J.Z.
Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A 4 Hydrolase.
Int J Mol Sci, 24:-, 2023

PubMed Abstract: The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A epoxide which is converted to a chemotactic leukotriene B (LTB) by leukotriene A hydrolase (LTAH). In addition, LTAH possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTAH, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTAH at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTAH with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB and can potentially be used as modulators of inflammatory response by the 5-LOX pathway.

PubMed: 37108702
DOI: 10.3390/ijms24087539

Experimental method

X-RAY DIFFRACTION (1.42 Å)