Date/Time
Date(s) - 30/01/2020
1:30 pm - 2:30 pm

TITLE:                       Tuning the Reactivity of Carbasugars to PermitTemporal Control of Glycoside Hydrolase Activity 

Date:                         Thursday, January 30, 2020

Time:                       1:30p.m.  

Place:                       ABB 165

Host:                       Dr. Anthony Rullo           

ABSTRACT:

 Tuning the Reactivity of Carbasugars to PermitTemporal Control of Glycoside Hydrolase Activity 

Theenzyme-catalyzed transfer of carbohydrates from a donor to an acceptor arecritical reactions for all life. As a result, the mechanisms for thesesubstitutions at the anomeric carbon of sugars have been studiedextensively.  Generally, these enzyme-catalyzed reactions occur by eithertwo inversions of configuration (retaining) or one (inverting).  The enzymethat hydrolysis glycosides are the glycoside hydrolases (GH), which have beengrouped into >165 families based on sequence and structure (Henrissat,B. 1991; Lombard,V., Ramulu, H. G. et al. 2014).

We have recently shownthat carbocyclic structural analogues of carbohydrates are mechanism-based covalent inhibitors of glycoside hydrolases (Shamsi Kazem Abadi, S., Tran, M. etal. 2017; Ren,W., Pengelly, R. et al. 2018). In order to understand how such covalentinhibitors react within the active site of glycoside hydrolases to giveinactive covalent enzyme intermediates, which undergoes a subsequent hydrolysisreaction to regenerate active enzyme, we have undertaken detailed mechanisticinvestigations of the reaction of these types of covalent inhibitors.  Ourstudies are a combination of the experimental determination of linear freeenergy relationship (LFER), kinetic isotope effects (KIEs) and hybrid quantummechanical/molecular mechanics (QM/MM) theoretical calculations.

Recentresults and their implication for the modes of action of these mechanism-basedcovalent inhibitors will be discussed.

References

[1]       Henrissat, B. (1991). A classification of glycosyl hydrolases based on aminoacid sequence similarities, Biochem. J. 280: 309-316.

[2]       Lombard, V., Ramulu, H.G., et al. (2014). The carbohydrate-active enzymesdatabase (CAZy) in 2013, Nucleic Acids Res. 42(D1): D490-D495.

[3]       Ren, W., Pengelly, R., et al. (2018). Revealing the mechanism for covalentinhibition of glycoside hydrolases by carbasugars at an atomic level, Nat.Commun. 9: 3243.

[4]       Shamsi Kazem Abadi, S., Tran, M., et al. (2017). New class of glycosidehydrolase mechanism-based covalent inhibitors: Glycosylation transition stateconformations, J. Am. Chem. Soc. 139: 10625–10628.