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

丝氨酸棕榈酰转移酶/鞘脂生物合成中第一个酶的结构和功能。

• 批准号: BB/F009739/1
• 负责人: Dominic Campopiano
• 金额: $ 38.71万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF009739%2F1
• 关键词: Serine; palmitoyltransferase; structure; function; first

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.

所有的细胞壁都必须坚韧耐用，并提供物理屏障以保护细胞免受外部因素的影响。它们必须将细胞内容物保持在内部，但也允许分子（例如营养素）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是相同的，并且开始于将氨基酸连接到脂肪酸。该反应由一种称为丝氨酸棕榈酰转移酶（SPT）的酶催化，并依赖于B族维生素辅因子。我们想了解鞘脂膜的分子细节。研究鞘脂化学和在人类和植物中制造它们的酶是困难的，因为构建模块和酶嵌入在膜中。为了更容易研究它们，它有助于将它们提取到水中，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脂，并且它的SPT酶可溶于水。我们可以纯化毫克量的这种SPT，我们最近已经确定了其原子分辨率的3D分子结构。我们现在想了解它是如何催化化学反应的，以及如何抑制它。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。鞘脂生成抑制剂可能成为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，已经发现有些人患有神经系统疾病，他们的SPT酶发生突变，因此我们也可以使用我们的模型来了解这些突变如何导致大脑中的spingolipid化学问题。

项目成果

Inhibition of the PLP-dependent enzyme serine palmitoyltransferase by cycloserine: evidence for a novel decarboxylative mechanism of inactivation.

• DOI: 10.1039/c003743e
• 发表时间: 2010-09
• 期刊: Molecular bioSystems
• 作者: Lowther J;Yard BA;Johnson KA;Carter LG;Bhat VT;Raman MC;Clarke DJ;Ramakers B;McMahon SA;Naismith JH;Campopiano DJ
• 通讯作者: Campopiano DJ

Prevalence of vertebral fracture in postmenopausal women with lumbar osteopenia using MorphoXpress® (OSTEOXPRESS Study).

使用 MorphoXpress®（OSTEOXPRESS 研究）了解腰椎骨质减少的绝经后妇女椎骨骨折的患病率。

• DOI: 10.3275/6799
• 发表时间: 2010
• 期刊: Aging clinical and experimental research
• 影响因子: 4
• 作者: Arboleya L