O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity.
O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity.
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DOI：
10.1007/s00726-014-1827-7
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发表时间：
2014-10
期刊：
影响因子：
3.5
通讯作者：
Ball LE
中科院分区：
文献类型：
--
作者：
Nagel AK;Ball LE
O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA）催化细胞内、翻译后O-GlcNAc修饰在细胞溶质、细胞核和线粒体信号蛋白的数千个Ser/Thr残基上的动态循环。O-GlcNAc修饰底物的鉴定揭示了一组功能多样的蛋白质，并且O-GlcNAc化的程度响应于营养和细胞应激而波动。因此，OGT和OGA参与了许多信号通路和转录程序的广泛的营养响应性调节。这些酶是正常胚胎发育所需的，在代谢和年龄相关疾病状态下失调。虽然最近在该领域的兴趣激增，有助于理解蛋白质O-GlcNAc酰化的功能影响，但对调节OGT和OGA底物靶向的上游机制知之甚少。这篇评论的重点是剪接变异体，翻译后修饰，本地化和调节蛋白质的相互作用，驱动OGT和OGA对细胞蛋白质组的不同子集的特异性之间的酶结构的元素。在这个快速发展的领域中正在进行的努力旨在揭示OGT和OGA调节的机制，以利用操纵这些酶活性的潜在治疗益处。
O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) catalyze the dynamic cycling of intracellular, post-translational O-GlcNAc modification on thousands of Ser/Thr residues of cytosolic, nuclear, and mitochondrial signaling proteins. The identification of O-GlcNAc modified substrates has revealed a functionally diverse set of proteins, and the extent of O-GlcNAcylation fluctuates in response to nutrients and cellular stress. As a result, OGT and OGA are implicated in widespread, nutrient-responsive regulation of numerous signaling pathways and transcriptional programs. These enzymes are required for normal embryonic development and are dysregulated in metabolic and age-related disease states. While a recent surge of interest in the field has contributed to understanding the functional impacts of protein O-GlcNAcylation, little is known about the upstream mechanisms which modulate OGT and OGA substrate targeting. This review focuses on elements of enzyme structure among splice variants, post-translational modification, localization, and regulatory protein interactions which drive the specificity of OGT and OGA toward different subsets of the cellular proteome. Ongoing efforts in this rapidly advancing field are aimed at revealing mechanisms of OGT and OGA regulation to harness the potential therapeutic benefit of manipulating these enzymes’ activities.