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Title 

Origin of the stereospecificity in binding hydroxamates of α- and β-phenylalanine methylamide to thermolysin revealed by the X-ray crystallographic study

Authors 

Seung-Jun KimD H KimJ D ParkJoo Rang WooY H JinSeong Eon Ryu

Publisher 

Elsevier

Issue Date 

2003

Citation 

Bioorganic & Medicinal Chemistry, vol. 11, no. 11, pp. 2421-2426

Keywords 

hydroxamic acid derivativen formyl n hydroxy alpha phenylalanine methylamiden formyl n hydroxy beta phenylalanine methylamiden hydroxy dextro phenylalanine methylamiden hydroxy n formyl dextro phenylalanine methylamiden hydroxy n formylphenylalanine methylamiden hydroxyphenylalanine methylamidephenylalanine derivativethermolysincomplex formation

Abstract 

Optically active N-formyl-N-hydroxy-α-phenylalanine methylamide (1) and N-formyl-N-hydroxy-β-phenylalanine methylamide (2) were evaluated as inhibitors for thermolysin (TLN) to find that while the D-form is more potent than its enantiomer in the case of the hydroxamate of α-Phe-NHMe, in the inhibition with hydroxamate of β-Phe-NHMe, the L-isomer (Ki=1.66±0.05 μM) is more effective than its enantiomer. In order to shed light on the stereochemical preference observed in the inhibitions, X-ray crystallographic analyses of the crystalline TLN·D-1 and TLN·L-2 complexes were performed to the resolution of 2.1 ?. While L-2 binds TLN like substrate does with its benzyl aromatic ring occupying the S1′ pocket, the electron density in the S1′ pocket in the complex of TLN·D-1 is weak and could best be accounted for by the methylcarbamoyl moiety. For both inhibitors, the hydroxamate moiety coordinates the active site zinc ion in a bidentate fashion.

ISSN 

0968-0896

Link 

http://dx.doi.org/10.1016/S0968-0896(03)00140-8

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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