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

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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.