Mechanistic Studies on the Formation of Glycosidase-Substrate and Glycosidase-Inhibitor Covalent Intermediates

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Natercia F Bras (Author) Other; Sara A Moura Tamames (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP

Journal

Title: Journal of Computational Chemistry

Vol. 29

Pages: 2565-2574

ISSN: 0192-8651

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 37 Citations

Scopus - 38 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-003-TTE

DOI: 10.1002/jcc.21013

Abstract (EN): Glycoside hydrolases catalyze the breaking of the glycosidic bond. This type of bond fashioned between two monosaccharides is very stable, and the polymers created are involved in multiple cellular processes, being crucial to life. In this article, computational methods were used to study the first step of the mechanism of reaction of retaining glycoside hydrolases in atomic detail. The systems modeled included a simplified reaction center and a small substrate/inhibitor. Using DFT calculations we were able to corroborate and provide molecular-level detail to the dissociative mechanism proposed in the literature. The role of the hydrogen bridge between the nucleophile and the C-2-OH group of the ring was also investigated. Therefore, we concluded that this bridge is responsible for lowering the activation barrier by 5.1 kcal mol(-1) with functional BB1K/6-311 +G(2d,2p), and the absence of the bridge explains, at least in part, the inhibitory effect of fluoro-substituted glycosides in the -2 position. The hydrogen bridge could also be involved in favoring the ring distortion verified in the transition state, and the dissociative character of the reaction mechanism. Using the NBO method, point atomic charges were calculated. In the transition state, the positive charge generated in the sugar ring is distributed nearly equally between the anomeric carbon and the ring oxygen, through a partial double bond involving the two atoms. (C) 2008 Wiley Periodicals, Inc. J Comput Chem 29: 2565-2574, 2008

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10