Bioorganic chemistry of tocopherol and lipid binding proteins

维生素E（大多数人称为a-生育酚）是一种脂溶性维生素，可以保护我们体内的脂肪（也称为脂质）免受氧化和酸败。即使在健康细胞中，这种损伤也会以背景速率发生-这是生活在含氧环境中的代价的一部分-但在氧化应激（如炎症，自身免疫性疾病和暴露于污染）期间可能会增加。不同的组织对维生素E有不同的需求。这就提出了一个问题：身体如何知道将饮食中的生育酚发送到需要它的组织中？我们已经制造出了看起来像天然维生素的分子，但是当光线照射到它们上时，它们会发出荧光。这使我们能够想象脂溶性维生素如何在充满水的细胞中移动。我们现在希望制造维生素E的形式，让我们确切地知道它喜欢在脂质膜中的什么地方度过它的时间。这对于了解维生素E的作用机制很重要。此外，某些形式的维生素E代谢非常快并排出体外。然而，其中一些形式具有独特的生物学特性，可以防止中风引起的神经元损伤。我们将制备这种代谢的抑制剂，使这些罕见形式的维生素E能够用于保护神经元。维生素E不溶于细胞内的水，因此需要特定的载体来运送分子。 哺乳动物肝脏中一种叫做生育酚转移蛋白（TTP）的蛋白质就能做到这一点。我们已经展示了TTP如何拾取生育酚并将其携带到细胞膜，细胞膜是由许多不同脂质组成的结构。 TTP喜欢粘附在某些脂质上，而不是其他脂质，事实上，它甚至喜欢导致膜弯曲而不是平坦的脂质。现在，我们希望利用我们在TTP方面的专业知识来研究其他也能在细胞周围移动脂质的蛋白质。 我们将重点关注的这两个家族负责转运胆固醇和构成膜的脂质等分子。 我们知道细胞有很多方法来控制这些蛋白质的工作方式，但没有人测量过蛋白质能多好地粘附在膜上，也没有人测量过它们是否喜欢粘附在某些膜上。

Vitamin E (known to most as a-tocopherol) is a fat-soluble vitamin that can protect the fats in our body (also known as lipids) from oxidizing and going rancid. Such damage occurs at a background rate even in healthy cells - part of the price of living in an oxygen-containing environment - but can increase during times of oxidative stress such as inflammation, autoimmune diseases, and exposure to pollution. Tissues have different demands for vitamin E. This raises a question: How does the body know to send dietary tocopherol to tissues where it is needed? We have made molecules that look like the natural vitamin, but that fluoresce when light is shone on them. This has allowed us to visualize how a fat-soluble vitamin moves around a water-filled cell. We now wish to make forms of vitamin E that would let us know exactly where in a lipid membrane it likes to spend its time. This is important for understanding how vitamin E works. Furthermore, some forms of vitamin E are metabolized very quickly and excreted. Some of these forms, however, have unique biological properties that might protect against the neuronal damage caused by strokes. We will prepare inhibitors of this metabolism that could enable the use of these rarer forms of vitamin E to protect neurons. Vitamin E is not soluble in the water inside of cells, and so needs specific carriers to ferry the molecule around. A protein in mammalian liver called the tocopherol transfer protein (TTP) accomplishes just this. We have shown how TTP can pick up tocopherol and carry it to a cell membrane, a structure composed of a number of different lipids. TTP likes to stick to some lipids and not others, indeed it even likes lipids that cause membranes to be curved rather than flat. We now wish to use our expertise with TTP to enquire of other proteins that also move lipids around cells. The two families that we will focus on are responsible for transporting molecules like cholesterol and the very lipids that make up membranes. We know that cells have many ways of controlling how these proteins work, but no one has measured how well the proteins can stick to membranes, nor whether they like to stick to certain membrane over others.