Membrane Interactions and Diacylglycerol Kinases

膜相互作用和二酰甘油激酶

• 批准号: 9848-2013
• 负责人: Epand, Richard
• 金额: $ 5.03万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=521303
• 关键词: Membrane; Interactions; Diacylglycerol; Kinases

Most lipids of biological membranes have a polar portion (headgroup) and a non-polar portion (acyl chains). There has been relatively little work done to understand the role of the acyl chains, yet certain acyl chains are heavily enriched in specific lipid classes. Prime examples of this sorting are the acyl chains of the lipid intermediates of the phosphatidylinositol cycle (PI-cycle) that are highly enriched in the 1-stearoyl-2-arachidonoyl species. The selective distribution of acyl chains has important consequences for the formation of specific molecular species of lipids that can act as signals, as well as to determine the physical properties of membrane domains. One enzyme contributing to the enrichment of specific acyl chains in the PI-cycle is the epsilon isoform of diacylglycerol kinase (DGKe). Among the ten isoforms of DGK found in mammals, DGKe is unique in having specificity for substrates with the particular acyl chains. We have also identified the segment of DGKe that is responsible for this recognition. This is leading to a fundamental understanding of how acyl chains are sorted to different lipids in the cell. One of the acyl chains that is recognized is the arachidonoyl group. This moiety is found in several different lipid signalling systems. We have evidence that there is a common recognition mechanism among all of these systems. Another DGK, DGKd, greatly increases its expression level after differentiation of 3T3-L1 cells to adipocytes. DGKd has a potent regulatory role in lipid metabolism. There is currently a poor understanding of the mechanism by which this occurs. We will determine the signal transduction pathway used by DGKd to regulate lipid synthesis. Our studies on the mechanism of metabolic regulation by DGKd will allow a development of an understanding of the pathways affected by this enzyme and the mechanism of this regulation. DGKd appears to have particular importance to biology, since it is the only isoform that results in non-viable offspring when knocked out.

生物膜的大多数脂质具有极性部分（头组）和非极性部分（酰基链）。为了了解酰基链的作用，所做的工作相对较少，但是某些酰基链在特定的脂质类别中大量丰富。这种排序的主要例子是磷脂酰肌醇循环（Pi-cycle）的脂质中间体的酰基链，它们高度富集在1 stearoyl-2-2-芳香酰种类中。酰基链的选择性分布对可以充当信号的特定分子物种的形成具有重要的后果，并确定膜结构域的物理特性。一种有助于富含比循环中特异性酰基链的酶是二酰基甘油激酶（DGKE）的Epsilon同工型。在哺乳动物中发现的DGK的十种同工型中，DGKE在具有特定酰基链的底物具有特异性方面是独一无二的。我们还确定了负责此识别的DGKE段。这导致对酰基链如何分类细胞中不同脂质的基本了解。被识别的酰基链之一是Arachidonoyl组。该部分在几个不同的脂质信号系统中发现。我们有证据表明，所有这些系统之间都有一种共同的识别机制。另一个DGK DGKD大大提高了3T3-L1细胞为脂肪细胞分化后其表达水平。 DGKD在脂质代谢中具有有效的调节作用。目前，人们对发生这种机制的理解很糟糕。我们将确定DGKD用于调节脂质合成的信号转导途径。我们对DGKD代谢调节机制的研究将允许对这种酶影响的途径以及该调节的机制进行理解。 DGKD似乎对生物学特别重要，因为这是唯一导致不可行后代的同工型。