O-GlcNAcylation and neurodegeneration

Wani, Willayat Yousuf; Chatham, John C.; Darley‐Usmar, Victor; McMahon, Lori L.; Zhang, Jianhua

doi:10.1016/j.brainresbull.2016.08.002

Cited by 102 publications

(93 citation statements)

References 92 publications

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“…Notably, O-GlcNAcylation has a complex interplay with phosphorylation, constituting an important mechanism to fine tune intracellular signaling 9,10 . Since O-GlcNAcylation is critical for normal physiology, its aberrant expression is closely associated with a number of diseases, including neurodegenerative diseases, diabetes, cardiovascular diseases, and cancers 8,[11][12][13] . Emerging research evidence indicates that O-GlcNAcylation is globally elevated in various cancers, but the mechanisms involved in the tumor pathology remain incompletely understood at the molecular level 14,15 .…”

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confidence: 99%

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

et al. 2020

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Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

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confidence: 99%

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

et al. 2020

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“…Glycan is synthesised on the ER membrane as a 14‐carbohydrate‐residue core moiety, which is attached to the target protein, trimmed and altered by glucosidases and mannosidases in the ER, and maturation occurs in the Golgi apparatus to produce complex glycosylated protein . Glycosylation is a sensor for metabolism mediated through the hexosamine biosynthetic pathway and different stress conditions, such as oxidative, osmotic and chemical stress, induce glycosylation . The glycosylation of a protein mediates several physiological processes, including cell–environment interactions, molecular recognition, signalling, host–pathogen interactions and immunological mechanisms .…”

Section: Glycosylationmentioning

confidence: 99%

Role of Post‐translational Modifications in Alzheimer's Disease

2020

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The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug‐discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post‐translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in‐depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease‐relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug‐discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.

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“…O‐glycosylation, which refers to the glycosylation that occurs on the oxygen atoms of the side chains of Ser/Thr/Tyr residues, is one of the most common post‐translational modifications (PTMs) and plays crucial roles in many biological and pathological processes including cell–cell adhesion and communication, protein–protein interaction, and immunization . O‐Glycosylation is initiated by transferring one of six different monosaccharides including α‐GalNAc, β‐GlcNAc, α‐Fuc, α‐Man, β‐Xyl, β‐Gal, and β‐Glc onto proteins .…”

Section: Introductionmentioning

confidence: 99%

Recent advances in methods for the analysis of protein o‐glycosylation at proteome level

You

Qin

2017

J of Separation Science

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O‐Glycosylation, which refers to the glycosylation of the hydroxyl group of side chains of Serine/Threonine/Tyrosine residues, is one of the most common post‐translational modifications. Compared with N‐linked glycosylation, O‐glycosylation is less explored because of its complex structure and relatively low abundance. Recently, O‐glycosylation has drawn more and more attention for its various functions in many sophisticated biological processes. To obtain a deep understanding of O‐glycosylation, many efforts have been devoted to develop effective strategies to analyze the two most abundant types of O‐glycosylation, i.e. O‐N‐acetylgalactosamine and O‐N‐acetylglucosamine glycosylation. In this review, we summarize the proteomics workflows to analyze these two types of O‐glycosylation. For the large‐scale analysis of mucin‐type glycosylation, the glycan simplification strategies including the ‘‘SimpleCell’’ technology were introduced. A variety of enrichment methods including lectin affinity chromatography, hydrophilic interaction chromatography, hydrazide chemistry, and chemoenzymatic method were introduced for the proteomics analysis of O‐N‐acetylgalactosamine and O‐N‐acetylglucosamine glycosylation.

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O-GlcNAcylation and neurodegeneration

Cited by 102 publications

References 92 publications

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

Role of Post‐translational Modifications in Alzheimer's Disease

Recent advances in methods for the analysis of protein o‐glycosylation at proteome level

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