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The O-GlcNAc dichotomy: when does adaptation become pathological?
Tiago J Costa1,2,3, Emily W Wilson1,2, Milene T Fontes1,2,3
1Cardiovascular Translational Research Center, University of South Carolina School of Medicine-Columbia, SC, U.S.A.
Abstract:
O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.
Insights
O-Linked N-acetylglucosamine (O-GlcNAc) is a dynamic protein modification impacting cellular functions. Chronic O-GlcNAcylation contributes to cardiovascular disease, offering potential therapeutic targets.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- O-Linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification affecting nuclear, cytoplasmic, and mitochondrial proteins.
- O-GlcNAcylation modulates cellular signaling and transcription in response to nutrients and stress, with thousands of proteins identified as targets.
- This modification is regulated by glucose metabolism via the hexosamine biosynthesis pathway, and its dysregulation is linked to metabolic abnormalities.
Approach:
- This review critically evaluates current literature on O-GlcNAcylation in vascular physiology.
- Focuses on the role of O-GlcNAcylation as a contributing mechanism in cardiovascular disease.
- Examines findings from genetically modified animal models to understand O-GlcNAcylation's impact.
Key Points:
- O-GlcNAcylation influences protein function, activity, localization, and stability.
- Acute O-GlcNAcylation is crucial for cellular signaling and transcription.
- Chronic O-GlcNAcylation is increasingly recognized as a factor in cardiovascular dysfunction.
Conclusions:
- O-GlcNAcylation, regulated by glucose metabolism, plays a significant role in vascular physiology.
- Elevated O-GlcNAc levels due to metabolic abnormalities are linked to cardiovascular disease.
- The O-GlcNAcylation pathway presents novel therapeutic targets for cardiovascular disease prevention and treatment.
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