A bittersweet modification: O-GlcNAc and cardiac dysfunction.
A bittersweet modification: O-GlcNAc and cardiac dysfunction.
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苦乐参半的修饰：O-GlcNAc 和心脏功能障碍。
DOI：
10.1161/01.res.0000168039.61228.67
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发表时间：
2005
影响因子：
20.1
通讯作者：
Jones,StevenP
中科院分区：
文献类型：
--
作者：
Jones,StevenP
Data from the Framingham Study indicate that cardiac dysfunction in diabetic patients may occur without documented cardiovascular disease. 1 Given the profound metabolic disturbance underlying diabetes, such dysfunction may not be surprising. Although it would be tempting to ascribe such dysfunction to simple energetic disturbances, a study in the current issue of Circulation Research 2 suggests a specific and rather unusual suspect in cardiac biology. The inability to handle glucose properly is a hallmark of diabetes. Of course, during any dialogue of glucose handling, discussants often focus on glycolysis or glycogen storage. Although up to 99% of intracellular glucose is destined for such fates, a small fraction (1% to 5%) of intracellular glucose is diverted to the hexosamine biosynthetic pathway which culminates in the formation of low millimolar levels of cytoplasmic uridine diphospho-N-acetylglucosamine (UDP-GlcNAc). Cells use cytoplasmic stores of UDP-GlcNAc for a variety of cell processes, but the present discussion focuses on one particular function: beta O-linkage of GlcNAc (O-GlcNAc) to intracellular proteins. Unlike Golgi-mediated cotranslational modifications associated with the serial N-linkage of sugars, the O-linkage of GlcNAc occurs posttranslationally and is highly dynamic. 3 There are 2 known enzymes regulating the presence of O-GlcNAc on proteins. Using UDP-GlcNAc as the monosaccharide donor, O-GlcNAc transferase (OGT) adds GlcNAc to proteins at serine or threonine residues whereas O-GlcNAcase removes the sugar moiety. Alterations in intracellular glucose flux can directionally change levels of the O-GlcNAc modification. Thus, a modified monosaccharide originating from glucose can function analogously to phosphorylation (O-phosphate linkage to proteins), the stereotypic posttranslational modification. Interestingly, O-GlcNAc modification and phosphorylation have been found to compete with one another for specific amino acid binding sites, further supporting the dynamic biological significance of O-GlcNAc modification. 4 Like phosphorylation, the O-GlcNAc modification imparts functional changes in target proteins and can affect transcription, translation, and signaling. 3, 5 O-GlcNAc may modulate a veritable panoply of cellular events including: proteasome function, 6 insulin resistance, 7 cell cycle control, 8 neutrophil function, 9 and possibly Alzheimer’s disease. 10 O-GlcNAc can occur at multiple serine or threonine sites on an ever-increasing catalog of proteins. Unlike the seemingly endless cavalcade of kinases and phosphatases associated with phosphorylation, only 2 enzymes regulate the existence of O-GlcNAc modifications on proteins. Such strict control of a seemingly ubiquitous process may reflect the role of O-GlcNAc as a metabolic, or nutrient, signal. 11 Most germane to the current study2 is the origin of the sugar core of the O-GlcNAc modification: glucose. During diabetes, glucose concentrations can become significantly elevated. Such elevations increase flux through the hexosamine biosynthetic pathway, thereby augmenting cytosolic UDP-GlcNAc levels. In such conditions, a net increase occurs in the abundance of O-GlcNAc modifications. To counteract this change and potentially incriminate excessive O-GlcNAc modifications in the pathophysiology of cardiac dysfunction during diabetes, Dillmann’s group2 used adenoviral gene transfer of O-GlcNAcase (ie, the enzyme that removes O-GlcNAc modification). The authors found that adenoviral transfer of O-GlcNAcase reversed the excessive O-GlcNAc modifications associated with diabetes, blunted the contractile abnormalities, and improved …
DOI：
10.1016/s0021-9258(17)43295-9
发表时间：
1984-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
C R Torres;G. W. Hart
通讯作者：
C R Torres;G. W. Hart
影响因子：
4.8
作者：
Cheng, XG;Hart, GW
通讯作者：
Hart, GW