Elucidating the molecular basis of nucleotide sugar transport in health and disease.

糖基化，即蛋白质被糖包裹的过程，发生在细胞的特殊区室中。然而，糖本身是在其他地方制造的，被称为核苷酸糖。它们必须通过一种叫做膜的不透水屏障被运送到专门的隔间里。进化通过使用称为转运蛋白的整体膜蛋白解决了这个难题，转运蛋白起着运河锁的作用，允许糖等分子穿过膜屏障。这些膜转运蛋白是如何工作的，目前是人们非常感兴趣的，因为它们是理解糖基化的原料，核苷酸糖，如何进入使用它们来使细胞糖基化的机制的关键。这项研究旨在了解糖分子是如何在人类、真菌和寄生虫细胞内运输的。一些致病生物利用含糖外衣逃避我们的免疫系统，造成广泛的疾病。一些真菌种类，特别是白色念珠菌和烟曲霉能够在接受器官移植或化疗的患者中建立感染。酵母菌感染每年在世界范围内造成数百万人死亡，并可在健康患者中建立慢性酵母菌感染，称为鹅口疮。在发展中国家，几种被称为锥虫的寄生虫使用类似的糖衣来躲避人类和牛的免疫细胞，从而在两者中引起毁灭性的疾病。幸运的是，这些生物体制造这些含糖防御系统所需的糖类型并不存在于人类细胞中，这使它们成为药物开发的诱人目标。本研究旨在了解核苷酸糖转运的特定膜蛋白是如何工作的。利用英国和国外最先进的设备，我们使用x射线探测运输蛋白的原子结构。这些信息将提供一个蓝图，告诉我们这些蛋白质是如何产生的，重要的是我们如何设计药物来阻止它们。这对于开发新的抗真菌和抗锥虫药物分子尤其重要。这项工作还将揭示由人体中负责核苷酸糖运输的转运体突变引起的几种发育和免疫疾病的基础。我们的研究将有助于提高我们对细胞糖基化的基础知识，影响人类，寄生虫和真菌细胞生物学的几个领域。

Glycosylation, the process by which proteins are coated with sugars, occurs in specialised compartments in the cell. However, the sugars themselves are manufactured elsewhere, and are called nucleotide sugars. They must be transported into the specialised compartments across an impermeable barrier, called a membrane. Evolution has solved this conundrum through the use of integral membrane proteins, called transporters, which act as canal locks, allowing molecules, such as sugars, to pass across the membrane barrier. How these membrane transporters work is currently of intense interest, as they hold the key to understanding how the raw materials for glycosylation, the nucleotide sugars, gain access to the machinery that uses them to glycosylate the cell. This research seeks to understand how sugar molecules are transported within human, fungal and parasite cells. Several pathogenic organisms use sugary coats to evade our immune system causing widespread diseases. Several fungal species, in particular Candida albicans and Aspergillus fumigatus are able to establish infections in patients undergoing organ transplant or chemotherapy. Yeast infections cause several million deaths each year worldwide and can establish chronic yeast infections in healthy patients, known as thrush. In the developing world, several species of parasites, called trypanosomes, use similar sugar coats to hide from immune cells in humans and cattle, causing devastating diseases in both. Fortunately, the type of sugar that these organisms need to create these sugary defence systems are not present in human cells, making them attractive targets for drug development. This proposal seeks to understand how the specific membrane proteins for nucleotide sugar transport work. Using state of the art facilities in the UK and abroad, we use X-rays to probe the atomic structure of the transport proteins. This information will provide a blue print that will tell us how these proteins are made and importantly how we can design drugs that stop them. This is particularly important for the development of new antifungal and anti-trypanosome drug molecules. This work will also reveal the basis for several developmental and immune diseases caused by mutations in the transporters responsible for nucleotide sugar transport in the human body. Our research will help to improve our fundamental knowledge of glycosylation in the cell, impacting several areas of human, parasite and fungal cell biology.