Serine palmitoyltransferase / structure and function of the first enzyme in sphingolipid biosynthesis.

所有的细胞壁都必须坚固耐用，并提供物理屏障来保护细胞免受外部因素的影响。它们必须将细胞内容物留在细胞内，但也允许分子(例如营养物质)进入细胞并将废物排出。人类、植物和细菌有不同的细胞壁成分，它们由许多称为鞘脂的复杂构件组成。最近发现，在所有物种中，鞘脂合成途径开始时的化学反应都是相同的，都是从连接氨基酸和脂肪酸开始的。这一反应是由一种名为丝氨酸棕榈酰转移酶(SPT)的酶催化的，并依赖于一种B维生素辅因子。我们想从分子上详细了解神经鞘脂膜是如何形成的。研究鞘脂化学和在人类和植物中制造鞘磷脂的酶是困难的，因为构建块和酶嵌入在膜中。为了更容易研究它们，将它们提取到水中是有帮助的，为此我们必须使用洗涤剂。不幸的是，这些酶在水中经常停止工作。然而，发现了一种细菌(称为鞘氨醇单胞菌)，它只产生一种类型的鞘磷脂，其SPT酶可溶于水。我们可以提纯毫克量的这种SPT，最近我们已经确定了它的3D分子结构，达到了原子分辨率。我们现在想了解它是如何催化化学反应的，以及它是如何被抑制的。事实证明，鞘脂不仅在细胞中发挥结构作用，而且还调节和控制细胞的工作方式。神经鞘脂生成的抑制剂可能会被证明是新的抗癌或抗炎药物。我们可以使用我们的细菌水溶性SPT结构作为人类膜结合酶的模型。此外，还发现一些人患有神经系统疾病，他们的SPT酶发生了突变，所以我们也可以利用我们的模型来了解这些突变是如何导致大脑中的棘脂化学问题的。

All cell walls have to be tough and durable and provide a physical barrier to protect the cell from external factors. They have to keep the cell contents inside but also allow molecules (e.g. nutrients) to pass into the cell and waste to leave. Humans, plants and bacteria have different cell wall components and they are made up of numerous complex building blocks called sphingolipids. It was recently discovered that the chemical reaction at the start of the sphingolipid synthetic pathway in all species is the same and begins by connecting an amino acid to a fatty acid. This reaction is catalysed by an enzyme called serine palmitoyltransferase (SPT) and is dependent on a B vitamin cofactor. We'd like to understand in molecular detail how sphingolipid membranes are made. Studying sphingolipid chemistry and the enzymes that make them in humans and plants is difficult because the building blocks and enzymes are embedded in membranes. To make it easier to study them, it helps to extract them into water and to do this we have to use detergents. Unfortunately, the enzymes often stop working in water. However, a bacterium (called Sphingomonas) was discovered that makes only one type of sphingolipid and its SPT enzyme is soluble in water. We can purify milligram amounts of this SPT and we have recently determined its 3D molecular structure to atomic resolution. We'd now like to understand how it catalyses the chemical reaction and how it can be inhibited. It turns out that sphingolipids not only play structural roles in cells, but also regulate and control the way the cell works. Inhibitors of sphingolipid production might turn out to be new anti-cancer or anti-inflammatory drugs. We can use our bacterial water-soluble SPT structure as a model for the human membrane-bound enzyme. Also, it has been discovered that some people have a neurological disease where their SPT enzyme is mutated so we can also use our model to understand how these mutations can cause problems with spingolipid chemistry in the brain.