Reduced Protein O-glycosylation in the Nervous System of the Mutant SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Peer reviewed: 
Yes, item is peer reviewed.
Scholarly level: 
Faculty/Staff
Final version published as: 

Shan, X., Vocadlo, D. J., & Krieger, C. (2012). Reduced protein O-glycosylation in the nervous system of the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neuroscience Letters, 516(2), 296–301. https://doi.org/10.1016/j.neulet.2012.04.018

Date created: 
2012-05-16
Identifier: 
DOI: 10.1016/j.neulet.2012.04.018
Keywords: 
O-glycosylation
Phosphorylation
O-GlcNAc
Neurofilament
NButGT
Amyotrophic lateral sclerosis
Abstract: 

Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with β-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts.

Language: 
English
Document type: 
Article
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Rights remain with the authors
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Sponsor(s): 
Canadian Institutes of Health Research (CIHR)
Scottish Rite Charitable Foundation (SRCF)
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