Effect of Modifier Structure on the Activation of Leukotriene A4 Hydrolase Aminopeptidase Activity

Activation of the leukotriene A4 hydrolase (LTA4H) aminopeptidase (AP) activity with 4-methoxydiphenylmethane (4MDM) promoted resolution of neutrophil infiltration in a murine cigarette smoke-induced model for emphysematous chronic obstructive pulmonary disease. Recently, 4-(4-benzylphenyl)­thiazol-...

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Veröffentlicht in:Journal of medicinal chemistry 2019-12, Vol.62 (23), p.10605-10616
Hauptverfasser: Lee, Kyung Hyeon, Petruncio, Greg, Shim, Amanda, Burdick, Marie, Zhang, Zhimin, Shim, Yun M, Noble, Schroeder M, Paige, Mikell
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Sprache:eng
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Zusammenfassung:Activation of the leukotriene A4 hydrolase (LTA4H) aminopeptidase (AP) activity with 4-methoxydiphenylmethane (4MDM) promoted resolution of neutrophil infiltration in a murine cigarette smoke-induced model for emphysematous chronic obstructive pulmonary disease. Recently, 4-(4-benzylphenyl)­thiazol-2-amine (ARM1) was published as a ligand for LTA4H with potential anti-inflammatory properties. To investigate the effect of modifier structure on enzyme kinetics of LTA4H, a series of analogues bearing structural features of ARM1 and 4MDM were synthesized using trifluoroborate Suzuki coupling reactions. Following, the 2.8 Å X-ray crystal structure of LTA4H complexed with 4-OMe-ARM1, a 4MDM-ARM1 hybrid molecule, was determined. Kinetic analysis showed that ARM1 and related analogues lowered affinity for the enzyme–substrate complex, resulting in a change of mechanism from hyperbolic mixed predominately catalytic activation (HMx­(Sp < Ca)­A) as observed for 4MDM to a predominately specific activation (HMx­(Sp > Ca)­A) mechanism. 4-OMe-ARM1 was then shown to dose responsively reduce LTB4 production in human neutrophils.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00663