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Synthesis of small molecule probes for muscular dystrophy-associated enzymes


   Department of Chemistry

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Background

Most proteins sitting at the surface of our cells are modified with a diversity of complex carbohydrate structures, or glycans. This process of protein glycosylation plays important roles in, for example, regulating communication between cells, cell-pathogen interactions, and cellular responses to external stimuli. Since glycans are not directly genetically encoded, their structures are highly dynamic: at any given time, the exact composition of cell-surface glycans is dictated by a complex network of cellular enzymes that create and modify the various glycan structures. This makes them incredibly hard to study. At the same time, defects in the functioning of one of the biosynthetic enzymes will lead to problems with the formation of the desired glycans, which in turn causes disease. However, the mechanism by which the malfunctioning of individual enzymes causes specific disease pathologies is often poorly understood.

The Willems group focuses on the development of novel chemical tools to advance our understanding of protein glycosylation. In particular, we aim to address important questions about how specific carbohydrate-processing enzymes work and how they are involved in the pathology of human disease, both at the molecular and the cellular level. The proposed project contributes to our work program by designing and synthesising novel enzyme probes for application to cell and structural biological studies.

Objectives

The specific form of glycosylation that our group is interested in is O-linked mannosylation, a relatively poorly understood type of glycosylation that is tightly connected to a subset of congenital muscular dystrophies. In this project, you will design and synthesise conceptually novel, small molecule probes that target some of the enzymes responsible for the biosynthesis of O-mannosyl glycans. These probes will allow us to visualise the target enzymes in vitro and inside cells, and will also enable diagnostic studies aimed at characterising enzyme activity levels in models of disease.

Experimental approach

The target probes are derived from the enzymes’ natural substrate, modified with two functional groups: 1) a bioorthogonal tag for further functionalisation (e.g. to introduce a fluorescent tag), and 2) an electrophilic trap or photo-affinity tag for covalent capturing of the target enzyme. Based on existing data on substrate binding in the proteins’ 3-D structures (obtained from x-ray crystallography or by modelling), you will design and screen various positions for the introduction of the two functional groups. The synthetic strategies to be used will involve a wide range of synthetic transformations starting from carbohydrate starting materials.

Novelty

Up until now, no probes have been published that report on the functional state of our set of target enzymes in their native, cellular context. By developing such probes, we will both facilitate fundamental studies aimed at enhancing our knowledge of the O-mannosylation pathway in vivo and also provide diagnostic tools that can be used to monitor, for example, enzyme activity in models of muscular dystrophies or to evaluate the effectiveness of novel therapeutics.

Training

Working on this project, you will be able to strengthen your knowledge and skills in a variety of chemical synthesis approaches and analytical techniques such as HPLC purification, LCMS and NMR characterisation. You will work closely with other group members, learning from their expertise and building on their experience, and you will receive additional training in specialist techniques as needed. You will also follow a cohort-based training programme (iDTC) to support your personal and professional development. Furthermore, you will participate in group meetings and (cross-)departmental seminars that will expose you to a variety of different research programmes and encourage a multidisciplinary way of thinking, with the work of close colleagues spanning organic synthesis, electro-chemistry, cell biology, molecular biology, biochemistry and protein crystallography.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/cdts/ 

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/ .


Funding Notes

This project is open to students who can fund their own studies or who have been awarded a scholarship separate from this project. The Chemistry Department at York is pleased to offer Wild Fund Scholarships to new students who will pay tuition fees at the overseas rate. Scholarships are competitive and awarded based on academic ability and financial need. For further information see: View Website

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