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7764388 
Journal Article 
Effect of Modifier Structure on the Activation of Leukotriene A4 Hydrolase Aminopeptidase Activity 
Lee, KH; Petruncio, G; Shim, A; Burdick, M; Zhang, Z; Shim, YM; Noble, SM; Paige, M 
2019 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
American Chemical Society 
62 
23 
10605-10616 
English 
31751136 
WOS:000503114200007 
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.