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.

大多数生物膜脂类具有极性部分(头基)和非极性部分(酰基链)。在了解酰基链的作用方面所做的工作相对较少，但某些酰基链在特定的脂类中大量富含。这种分类的主要例子是磷脂酰肌醇循环(PI-循环)的脂类中间体的酰基链，它高度富含1-硬脂酰基-2-花生四烯酰基物种。酰基链的选择性分布对特定的脂类分子物种的形成具有重要的影响，这些分子物种可以作为信号，并决定膜结构域的物理性质。在PI循环中，有助于丰富特定酰基链的一种酶是二酰基甘油激酶(DGKe)的epsilon异构体。在哺乳动物中发现的十种DGK亚型中，DGKe的独特之处在于对具有特定酰基链的底物具有特异性。我们还确定了DGKe中负责这一识别的部分。这使我们从根本上理解了酰基链是如何与细胞中不同的脂类分类的。已知的一种酰基链是花生四烯酰基。该部分存在于几种不同的脂质信号系统中。我们有证据表明，所有这些系统之间都有一个共同的识别机制。另一种DGK，DGKd，在3T3-L1细胞分化为脂肪细胞后，显著提高了其表达水平。DGKD对脂代谢有很强的调节作用。目前，人们对这种情况发生的机制了解很少。我们将确定DGKD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有助于理解这种酶影响的途径和这种调节的机制。DGKd似乎对生物学具有特别重要的意义，因为它是唯一一种在被敲除后导致无法存活的后代的亚型。