Chemical approaches to perturb, profile, and perceive glycans.
Chemical approaches to perturb, profile, and perceive glycans.
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DOI：
10.1021/ar800267j
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发表时间：
2009-06-16
影响因子：
18.3
通讯作者：
Bertozzi, Carolyn R.
中科院分区：
文献类型：
--
作者：
Agard, Nicholas J.;Bertozzi, Carolyn R.
糖基化是一种重要的翻译后修饰形式，调节细胞内和细胞外过程。遗憾的是，传统的生物化学和遗传学方法往往不足以研究聚糖，因为它们的结构往往不能在遗传水平上精确定义。为了解决这一缺陷，化学家们开发了一些技术来干扰聚糖的生物合成，在系统水平上分析它们的表达，并感知它们的空间分布。这些工具已经确定了潜在的疾病生物标志物和监测生物体内糖组动态变化的方法。尽管如此，糖基化仍然是许多生物系统的未充分探索的前沿。在这个账户中，我们专注于我们实验室的研究，旨在将聚糖功能的研究从挑战转变为常规实践。在蛋白质和核酸的研究中，功能研究通常依赖于基因操作来扰乱结构。虽然不直接发生突变，但我们可以通过合成确定的糖缀合物或通过改变天然糖基化途径来确定聚糖的结构-功能关系。化学合成的统一的糖蛋白和多聚糖蛋白模拟物，促进了个别糖缀合物的研究，在聚糖微观异质性的情况下。或者，糖基转移酶或糖苷酶的选择性抑制或激活可以定义相应聚糖的生物学作用。研究人员已经开发出包括小分子抑制剂、诱饵底物和工程蛋白质在内的工具来修饰细胞聚糖。目前的方法提供了接近遗传控制的精确度。基因组和蛋白质组分析是生物学发现的基础。聚糖还提供了丰富的信息矩阵，可以快速适应不断变化的环境。通过微阵列和质谱的糖组学和糖蛋白质组学分析开始表征与疾病相关的聚糖的改变。这些方法已经确定了几种癌症生物标志物。代谢标记可以识别最近合成的聚糖，从而直接跟踪聚糖动力学。这种方法可以突出显示生理或环境的变化，并且可能比稳态分析提供更多信息。糖组学和代谢标记技术共同提供了糖基化的全面描述，作为假设生成的基础。通过绿色荧光蛋白（GFP）及其同源物直接可视化蛋白质已经彻底改变了蛋白质动力学领域。同样，感知聚糖空间组织的能力可以改变我们对它们在发育，感染和疾病进展中的作用的理解。在培养细胞和发育中的生物体中的荧光标记揭示了对这些结构在生长和发育期间的动态的重要见解。这些结果强调了对额外成像探针的需求。
Glycosylation is an essential form of post-translational modification that regulates intracellular and extracellular processes. Regrettably, conventional biochemical and genetic methods often fall short for the study of glycans, because their structures are often not precisely defined at the genetic level. To address this deficiency, chemists have developed technologies to perturb glycan biosynthesis, profile their presentation at the systems level, and perceive their spatial distribution. These tools have identified potential disease biomarkers and ways to monitor dynamic changes to the glycome in living organisms. Still, glycosylation remains the underexplored frontier of many biological systems. In this Account, we focus on research in our laboratory that seeks to transform the study of glycan function from a challenge to routine practice. In studies of proteins and nucleic acids, functional studies have often relied on genetic manipulations to perturb structure. Though not directly subject to mutation, we can determine glycan structure−function relationships by synthesizing defined glycoconjugates or by altering natural glycosylation pathways. Chemical syntheses of uniform glycoproteins and polymeric glycoprotein mimics have facilitated the study of individual glycoconjugates in the absence of glycan microheterogeneity. Alternatively, selective inhibition or activation of glycosyltransferases or glycosidases can define the biological roles of the corresponding glycans. Investigators have developed tools including small molecule inhibitors, decoy substrates, and engineered proteins to modify cellular glycans. Current approaches offer a precision approaching that of genetic control. Genomic and proteomic profiling form a basis for biological discovery. Glycans also present a rich matrix of information that adapts rapidly to changing environs. Glycomic and glycoproteomic analyses via microarrays and mass spectrometry are beginning to characterize alterations in glycans that correlate with disease. These approaches have already identified several cancer biomarkers. Metabolic labeling can identify recently synthesized glycans and thus directly track glycan dynamics. This approach can highlight changes in physiology or environment and may be more informative than steady-state analyses. Together, glycomic and metabolic labeling techniques provide a comprehensive description of glycosylation as a foundation for hypothesis generation. Direct visualization of proteins via the green fluorescent protein (GFP) and its congeners has revolutionized the field of protein dynamics. Similarly, the ability to perceive the spatial organization of glycans could transform our understanding of their role in development, infection, and disease progression. Fluorescent tagging in cultured cells and developing organisms has revealed important insights into the dynamics of these structures during growth and development. These results have highlighted the need for additional imaging probes.
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影响因子：
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通讯作者：
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