GLYCOPOISE · Glycosylation: Programmes for Observation, Inhibition and Structure-based Exploitation of key carbohydrate-active enzymes

The development of new approaches to dissect the diverse roles for carbohydrates in living cells is a major challenge for modern cell biology. The huge diversity of carbohydrates is reflected in a multiplicity of function; in addition to acting as energy sources, carbohydrates play major roles in structure, signalling and epigenetics. The work programme will build upon the applicant’s excellence in the mechanistic and structural enzymology of carbohydrate-active enzymes to tackle the key challenges of modern cellular glycobiology. Our vision is to provide fundamental structural and mechanistic-dissection of key proteins and their complexes and to use these as the foundation to deliver enzyme inhibitors as tools to probe the cellular function of specific glycans. The programme’s three strands will each scale a major pinnacle of carbohydrate biochemistry. Strand 1 will focus on mammalian glycosidases involved in glycocerebroside metabolism and genetic disease. We will unlock new 3-D information for glycocerebrosidase 2 (GBA2) and use these together with GBA1 to design and exploit novel and specific enzyme inhibitors as mechanistic and cellular probes, novel chaperones and imaging agents. Strand 2 will focus on the key endoplasmic reticulum enzyme endomannosidase, both its mechanistic novelty and its exploitation to perturb cellular glycans to unlock its biological roles and deliver compounds for anti-viral therapeutics. Strand 3 will probe the modification and elaboration of specific human N-glycans and their role in cell surface receptor biology. It will focus on the GlcNAc transferase V catalysed formation of polylactosamine epitopes and their regulation of growth factor signalling at the cell surface both in health and cancerous tissues. GlycoPOISE will both answer cardinal structural and chemical mechanistic questions in the enzymology of glycobiology and inform strategies for the observation and inhibition of carbohydrate-active enzymes and their exploitation