A QM/MM approach on the structural and stereoelectronic factors governing glycosylation by GTF-SI from Streptococcus mutans

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Jana, GA (Author) Other; Mendoza, F (Author) Other; Osorio, MI (Author) Other; Alderete, JB (Author) Other; Pedro A Fernandes (Author) FCUP; Ramos, MJ (Author) FCUP; Jimenez, VA (Author) Other

Journal

Title: Organic and Biomolecular Chemistry

Vol. 16

Pages: 2438-2447

ISSN: 1477-0520

Publisher: Royal Society of Chemistry

Indexing

ISI Web of Knowledge - 8 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00N-V80

DOI: 10.1039/c8ob00284c

Abstract (EN): In this work, QM/MM calculations were employed to examine the catalytic mechanism of the retaining glucosyltransferase GTF-SI enzyme, which participates in the process of caries formation. Our goal was to characterize, with atomistic details, the mechanism of sucrose hydrolysis and the catalytic factors that modulate this reaction. Our results suggest a concerted mechanism for sucrose hydrolysis in which the first event corresponds to the glycosidic bond breakage assisted by Glu515, followed by the nucleophilic attack of Asp477, leading to the formation of the Covalent Glycosyl Enzyme (CGE) intermediate. A novel conformational itinerary of the glucosyl moiety along the reaction mechanism was identified: H-2(3) H-2(3)-E-3 C-4(1), and the calculated energy barrier is 16.4 kcal mol(-1), which is in good agreement with experimental evidence showing a major contribution coming from the glycosidic bond breakage. Our calculations also revealed that Arg475 and Asp588 play a critical role as TS-stabilizers by electrostatic and charge transfer mechanisms, respectively. This is the first report dealing with the specific features of the mechanism and catalytic residues involved in GTF-SI hydrolysis of sucrose, which is a matter of relevance in enzyme catalysis and could be valuable to aid the design of novel and specific inhibitors targeting GTF-SI.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10