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. 2012 May 15;302(10):H1905-18.
doi: 10.1152/ajpheart.00445.2011. Epub 2012 Jan 27.

The Roles of O-linked β-N-acetylglucosamine in Cardiovascular Physiology and Disease

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The Roles of O-linked β-N-acetylglucosamine in Cardiovascular Physiology and Disease

Natasha E Zachara. Am J Physiol Heart Circ Physiol. .
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More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β-N-acetylglucosamine (O-GlcNAc), an essential post-translational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature.


Fig. 1.
Fig. 1.
Metabolism of the O-linked β-N-acetylglucosamine (O-GlcNAc) modification. A small percentage of glucose imported into the cell is converted through the hexosamine biosynthetic pathway to UDP-GlcNAc. UDP-GlcNAc is the high-energy sugar donor for glycosylation by the O-GlcNAc transferase (OGT) and glycosylation in the endoplasmic reticulum and Golgi apparatus. Glucosamine and glutamine (orange) can be used for the synthesis of UDP-GlcNAc. Thiamet-G and O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc; red) are commercially available inhibitors of the O-GlcNAcase, the enzyme that removes O-GlcNAc. Notably, on a subset of proteins, the O-GlcNAc modification site is the same as that reported for phosphorylation. Thus, for some proteins, there is a reciprocal relationship between phosphorylation and the O-GlcNAc modification. In support of this model, OGT has been found in a complex with protein phosphatase 1α and γ, and during cytokinesis, OGT and O-GlcNAcase are found in a complex together and with protein phosphatase 1 and aurora kinase B. Gene names are as follows: Gfpt1, glutamine fructose-6-phosphate transaminase 1 (GFAT); Gnpnat1, glucosamine-phosphate N-acetyltransferase 1; Pgm3, phosphoglucomutase 3; Uap1, UDP-N-acetylglucosamine pyrophosphorylase 1.

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