ERC Synergy Grant to unlock sugar codes for health and a sustainable society
Hermen Overkleeft and his colleagues Gideon Davies (University of York) and Carme Rovira (University of Barcelona) will receive a 9.1 million euros Synergy Grant from the European Research Council. Together, they will form the Carbocentre Synergy team for research into enzymes that work on glycans: complex carbohydrates. ‘Unlocking the biology of these sugars can have major ramifications for human health and a sustainable society.’
Carbohydrates have mind-boggling chemical diversity. They are the most abundant and diverse class of biomolecules on Earth. The synthesis, modification and breakdown of carbohydrates is regulated by enzymes, or natural catalysts, but much is still unknown. The Carbocentre Synergy team will now develop novel chemical compounds, called ‘activity-based probes’ (see box below) to visualise, modulate and understand the work of these enzymes.
On 5 November The European Research Council (ERC) announced the 2020 Synergy Grants. These prestigious European grants are awarded for collaborative, curiosity-driven research executed by teams of world-class researchers coming together to tackle major scientific challenges.
Unlock the code
‘Carbohydrates are all around us’, says Hermen Overkleeft, who will lead the Carbocentre team. ‘They are the language of cells, our cellular bar-codes, but they are also incredibly complex. Once we have the tools to decipher nature’s glyco-codes, we can begin to unlock their biology for societal benefit. Think of applications for human health or sustainable energy. It is fabulous to be working with two world class groups in this major endeavor.’
Health and sustainability
Many viruses, including Influenza and Covid-19, use glycans for cellular entry and as part of their structure. Many human diseases rooted in carbohydrate chemistry. ‘Our collaborative work will provide truly disruptive technologies for health, to fight cancer, genetic disease and viral invasions,’ says Davies. ‘But it will also allow the discovery and characterisation of enzymes for biomass degradation leading to green energy solutions. This ERC Synergy grant will enable groups in Barcelona, Leiden and York to tackle these major societal challenges.’
Synergy for insight
The team will harness computational and structural analyses of how enzymes work and use that to inform chemical synthesis of activity-based probes that allow the detection, imaging and isolation of these enzymes in living systems.
‘The three teams have an incredible synergy’, says Rovira, who will lead the computational strand. ‘It will be wonderful to see how computation, structure and organic chemistry can come together for major biological insight.’
In order for an enzyme to fulfill its task, it needs to bind to a substrate. Activity-based probes (ABPs) are small sugar-like molecules that bind to an enzyme as if they were substrates, and then remain irreversibly bound.
This way, you can use ABP’s to ‘fish’ for unknown enzymes in the body. The nature of the ABP structure then informs on the substrate preference of this tagged enzyme, even if other (structural, genetic) information is still lacking.
ABPs can be used to diagnose tissue from patients suffering from one of the several rare diseases associated to glycoprocessing enzymes (for instance in Gaucher disease, a glycogen storage disorder in which the enzyme lysosomal β-glucosidase is absent). Furthermore, ABPs can be used as inhibitors to stop harmful enzymes from making you sick.
ABPs can equally be applied in biotechnology, to dissect the complex secreted enzyme repertoire of biomass-degrading fungi and bacteria, boosting the discovery of new enzymes for biofuel production.