The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Gideon J. Davies; Carlos Martinez-Fleites

doi:10.1042/BST0381179

The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Gideon J. Davies, Carlos Martinez-Fleites

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Carbohydrates, their structures and the enzymes responsible for their synthesis and degradation, offer numerous possibilities for the design and application of probes with which to study and treat disease. The intracellular dynamic O-GlcNAc (O-linked beta-N-acetylglucosamine) modification is one such glycosylation with considerable medical interest, reflecting its implication in diseases such as Type 2 diabetes and neurodegeneration. In the present paper, we review recent structural and mechanistic studies into the enzymes responsible for this modification, highlighting how mechanism-inspired small-molecule probes may be applied to study potential disease processes. Such studies have questioned a causal link between O-GlcNAc and Type 2 diabetes, but do offer potential for the study, and perhaps the treatment, of tauopathies.

Original language	English
Pages (from-to)	1179-1188
Number of pages	10
Journal	Biochemical Society transactions
Volume	38
Issue number	5
DOIs	https://doi.org/10.1042/BST0381179
Publication status	Published - Oct 2010

Keywords

carbohydrate-active enzyme
diabetes
neurodegeneration
O-linked beta-N-acetylglucosamine (O-GlcNAc)
X-ray structure
BETA-N-ACETYLGLUCOSAMINIDASE
LINKED GLCNAC
INSULIN-RESISTANCE
TRANSITION-STATE
SUBSTRATE DISTORTION
NUCLEOCYTOPLASMIC PROTEINS
MECHANISTIC INSIGHTS
REACTION COORDINATE
ALZHEIMERS-DISEASE
3T3-L1 ADIPOCYTES

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10.1042/BST0381179

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title = "The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease",

abstract = "Carbohydrates, their structures and the enzymes responsible for their synthesis and degradation, offer numerous possibilities for the design and application of probes with which to study and treat disease. The intracellular dynamic O-GlcNAc (O-linked beta-N-acetylglucosamine) modification is one such glycosylation with considerable medical interest, reflecting its implication in diseases such as Type 2 diabetes and neurodegeneration. In the present paper, we review recent structural and mechanistic studies into the enzymes responsible for this modification, highlighting how mechanism-inspired small-molecule probes may be applied to study potential disease processes. Such studies have questioned a causal link between O-GlcNAc and Type 2 diabetes, but do offer potential for the study, and perhaps the treatment, of tauopathies.",

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author = "Davies, {Gideon J.} and Carlos Martinez-Fleites",

year = "2010",

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AU - Martinez-Fleites, Carlos

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N2 - Carbohydrates, their structures and the enzymes responsible for their synthesis and degradation, offer numerous possibilities for the design and application of probes with which to study and treat disease. The intracellular dynamic O-GlcNAc (O-linked beta-N-acetylglucosamine) modification is one such glycosylation with considerable medical interest, reflecting its implication in diseases such as Type 2 diabetes and neurodegeneration. In the present paper, we review recent structural and mechanistic studies into the enzymes responsible for this modification, highlighting how mechanism-inspired small-molecule probes may be applied to study potential disease processes. Such studies have questioned a causal link between O-GlcNAc and Type 2 diabetes, but do offer potential for the study, and perhaps the treatment, of tauopathies.

AB - Carbohydrates, their structures and the enzymes responsible for their synthesis and degradation, offer numerous possibilities for the design and application of probes with which to study and treat disease. The intracellular dynamic O-GlcNAc (O-linked beta-N-acetylglucosamine) modification is one such glycosylation with considerable medical interest, reflecting its implication in diseases such as Type 2 diabetes and neurodegeneration. In the present paper, we review recent structural and mechanistic studies into the enzymes responsible for this modification, highlighting how mechanism-inspired small-molecule probes may be applied to study potential disease processes. Such studies have questioned a causal link between O-GlcNAc and Type 2 diabetes, but do offer potential for the study, and perhaps the treatment, of tauopathies.

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KW - LINKED GLCNAC

KW - INSULIN-RESISTANCE

KW - TRANSITION-STATE

KW - SUBSTRATE DISTORTION

KW - NUCLEOCYTOPLASMIC PROTEINS

KW - MECHANISTIC INSIGHTS

KW - REACTION COORDINATE

KW - ALZHEIMERS-DISEASE

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JO - Biochemical Society transactions

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IS - 5

ER -

The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Abstract

Keywords

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