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

Streptococcus mutans

Gonzalo A. Jaña, Fernanda Mendoza, Manuel I. Osorio, Joel B. Alderete, Pedro A. Fernandes, Maria J. Ramos, Verónica A. Jiménez

Resultado de la investigación: Article

2 Citas (Scopus)

Resumen

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: 2H32H3-E34C1, 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.

Idioma originalEnglish
Páginas (desde-hasta)2438-2447
Número de páginas10
PublicaciónOrganic and Biomolecular Chemistry
Volumen16
N.º14
DOI
EstadoPublished - 1 ene 2018

Huella dactilar

streptococcus
Glycosylation
Streptococcus mutans
International System of Units
Sucrose
Hydrolysis
sucrose
Enzymes
Glucosyltransferases
hydrolysis
enzymes
Energy barriers
Static Electricity
Catalysis
Charge transfer
Electrostatics
retaining
inhibitors
attack
catalysis

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Citar esto

Jaña, Gonzalo A. ; Mendoza, Fernanda ; Osorio, Manuel I. ; Alderete, Joel B. ; Fernandes, Pedro A. ; Ramos, Maria J. ; Jiménez, Verónica A. / A QM/MM approach on the structural and stereoelectronic factors governing glycosylation by GTF-SI from : Streptococcus mutans. En: Organic and Biomolecular Chemistry. 2018 ; Vol. 16, N.º 14. pp. 2438-2447.
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abstract = "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: 2H3 → 2H3-E3 → 4C1, 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.",
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A QM/MM approach on the structural and stereoelectronic factors governing glycosylation by GTF-SI from : Streptococcus mutans. / Jaña, Gonzalo A.; Mendoza, Fernanda; Osorio, Manuel I.; Alderete, Joel B.; Fernandes, Pedro A.; Ramos, Maria J.; Jiménez, Verónica A.

En: Organic and Biomolecular Chemistry, Vol. 16, N.º 14, 01.01.2018, p. 2438-2447.

Resultado de la investigación: Article

TY - JOUR

T1 - A QM/MM approach on the structural and stereoelectronic factors governing glycosylation by GTF-SI from

T2 - Streptococcus mutans

AU - Jaña, Gonzalo A.

AU - Mendoza, Fernanda

AU - Osorio, Manuel I.

AU - Alderete, Joel B.

AU - Fernandes, Pedro A.

AU - Ramos, Maria J.

AU - Jiménez, Verónica A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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: 2H3 → 2H3-E3 → 4C1, 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.

AB - 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: 2H3 → 2H3-E3 → 4C1, 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.

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