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

阐明健康和疾病中核苷酸糖转运的分子基础。

• 批准号: MR/S021043/1
• 负责人: Simon Newstead
• 金额: $ 76.72万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021043%2F1
• 关键词: Elucidating; molecular; basis; nucleotide; sugar

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.

糖基化是蛋白质被糖包裹的过程，发生在细胞的专门区域。然而，糖本身是在其他地方制造的，被称为核苷酸糖。它们必须穿过一个叫做膜的不渗透屏障被运送到专门的隔间里。进化已经解决了这个难题，通过使用完整的膜蛋白，称为转运蛋白，它作为运河锁，允许分子，如糖，通过膜屏障。这些膜转运蛋白如何工作目前引起了人们的强烈兴趣，因为它们是理解糖基化的原材料核苷酸糖如何进入使用它们使细胞糖基化的机制的关键。这项研究旨在了解糖分子如何在人类，真菌和寄生虫细胞内运输。几种病原体使用糖衣来逃避我们的免疫系统，引起广泛的疾病。几种真菌物种，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。酵母菌感染每年在全世界造成数百万人死亡，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，这些生物体创建这些含糖防御系统所需的糖类型并不存在于人类细胞中，这使得它们成为药物开发的有吸引力的目标。该提案旨在了解核苷酸糖转运的特定膜蛋白如何工作。使用英国和国外最先进的设施，我们使用X射线来探测转运蛋白的原子结构。这些信息将提供一个蓝图，告诉我们这些蛋白质是如何制造的，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特别重要。这项工作还将揭示几种发育和免疫疾病的基础，这些疾病是由负责人体内核苷酸糖转运的转运蛋白突变引起的。我们的研究将有助于提高我们对细胞中糖基化的基础知识，影响人类，寄生虫和真菌细胞生物学的几个领域。

项目成果

Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.

• DOI: 10.1126/sciadv.abh3355
• 发表时间: 2021-08
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Parker JL;Deme JC;Wu Z;Kuteyi G;Huo J;Owens RJ;Biggin PC;Lea SM;Newstead S
• 通讯作者: Newstead S

Molecular basis for redox control by the human cystine/glutamate antiporter System xc -

人胱氨酸/谷氨酸逆向转运蛋白系统 xc 氧化还原控制的分子基础 -

• DOI: 10.1101/2021.08.09.455631
• 发表时间: 2021
• 作者: Parker J

Molecular basis for selective uptake and elimination of organic anions in the kidney by OAT1.

• DOI: 10.1038/s41594-023-01039-y
• 发表时间: 2023-11
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Parker, Joanne L.;Kato, Takafumi;Kuteyi, Gabriel;Sitsel, Oleg;Newstead, Simon
• 通讯作者: Newstead, Simon

Structural basis of antifolate recognition and transport by PCFT.

• DOI: 10.1038/s41586-021-03579-z
• 发表时间: 2021-07
• 期刊: Nature
• 影响因子: 64.8