Defining the Heart and Cardiovascular O-GlcNAcome

The modification of nuclear, cytoplasmic, and mitochondrial proteins by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc) was first reported in 1984.1,2 Recent proteomic screens suggest that >1000 proteins in the cell are modified by O-GlcNAc3–10 and that these O-GlcNAc–modified proteins fall into many functional groups, including transcription factors and polymerases, cytoskeletal proteins, kinases and phosphatases, metabolic enzymes, ribosomal proteins, proteasomal proteins, and viral proteins.3–10 Not surprisingly, deletion of the O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, is lethal in mice at E4.5 and in isolated embryonic fibroblasts.11,12O-GlcNAc is thought to regulate protein function in a manner analogous to protein phosphorylation,13 and like protein phosphorylation, levels of the O-GlcNAc protein modification, or O-GlcNAcylation, respond to numerous signals, including cellular damage, such as that caused by ischemia-reperfusion injury.13,14 Importantly, for a subset of proteins, O-GlcNAc and phosphorylation appear to be reciprocal, because the site of O-GlcNAcylation and phosphorylation is the same or, alternatively, the sites are proximal to each other.13 Supporting a model in which proteins are dynamically cycled between O-GlcNAcylated and phosphorylated states, the O-GlcNAc transferase is found in a complex with protein phosphatases.13,15Unlike protein phosphorylation, the addition and removal of O-GlcNAc is catalyzed by just 2 enzymes, the O-GlcNAcase (removes O-GlcNAc) and the O-GlcNAc transferase (adds O-GlcNAc).13 The high-energy sugar donor used by OGT is UDP-GlcNAc. A fraction (2–5% in adipocytes) of glucose imported into the cell is converted to UDP-GlcNAc through the hexosamine biosynthetic pathway; as such, O-GlcNAc is thought to be an effector of glucose, as well as glutamine and glucosamine (Figure 1).13 These observations, and other studies, have led to the idea that elevated levels of O-GlcNAc are involved in mediating some of …