Effect of Modifier Structure on the Activation of Leukotriene A4 Hydrolase Aminopeptidase Activity
| Autor: | Amanda Shim, Kyung Hyeon Lee, Zhimin Zhang, Mikell Paige, Schroeder M. Noble, Yun M. Shim, Greg Petruncio, Marie D. Burdick |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Chemistry Stereochemistry Crystal structure 01 natural sciences Aminopeptidase 0104 chemical sciences Catalysis Leukotriene-A4 hydrolase 010404 medicinal & biomolecular chemistry 03 medical and health sciences Suzuki reaction Drug Discovery Hydrolase Molecular Medicine Molecule Enzyme kinetics 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:10605-10616 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 A 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) mechanism. 4-OMe-ARM1 was then shown to dose responsively reduce LTB4 production in human neutrophils. |
| Databáze: | OpenAIRE |
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