Title: What features of bacterial carbohydrate sulfatases can be exploited for human health?
Funder: The Academy of Medical Sciences

Abstract: De-sulfation of carbohydrates is required for cell signalling and development, and is essential for the recycling and utilisation of these biomolecules. Sulfated glycans are also important in maintaining a healthy bacterial gut microbiota. The Human Gut Microbiota (HGM) is a vast microbial community that is essential for maintaining human health. It provides a protective barrier against pathogens, trains and regulates our immune system and provides up to 10 % of our daily calories. This community thrives by degrading complex glycans with some members of the HGM, such as the model organism Bacteroides thetaiotaomicron (B.theta), dedicating up to 20 % of its genome to glycan degradation. Sulfated glycans, in the form of glycosaminoglycans (GAGs) and sulfomucins, are important carbohydrate resources for the HGM and carbohydrate sulfatases are essential for their metabolism. GAGs are a high priority glycan resources for B.theta meaning they are utlised ahead of other glycans. The reasons why GAGs are prioritised so highly is unknown, but sulfatases are essential for their metabolism. Thus, small molecules that can be developed to modify GAG sulfatase function could be used to probe GAG utilisation and as potential pre-biotics to modify the HGM composition. Carbohydrate sulfatase of the HGM are also required for the degradation of the protective sulfomucin layer, which lines the large intestine. Excessive degradation, however, leads to inflammatory bowel diseases such as colitis and Crohns disease and is implicated in colorectal cancer. This makes mucin sulfatases drug targets and inhibitors could alleviate the aforementioned diseases.

Lay abstract: Sulfation is a key biological process and dramatically alters the properties of molecules on which it occurs. Enzymes known as sulfotransferases and sulfatases, respectively, carry out the process of sulfation and de-sulfation. In humans many carbohydrates crucial to biological processes, such as cell signalling and cell protection from bacteria, require sulfation. Recently the roles played by sulfatases in human disease, in particular bacterial sulfatases of the digestive system, have become much more prevalent, and currently there is a large knowledge gap of the how these enzymes function at the molecular level. Bacterial sulfatases produced by 'friendly' bacteria that inhabit our digestive system can cause chronic conditions such as colitis and Crohns disease, and colorectal cancers. In this instance over activity of the sulfatases degrades the protective sulfated polysaccharide layer (mucin) allowing normally friendly bacteria to come into close a contact with our own cells and thus causing these disease states. It is my goal to study sulfatases at the molecular level to understand their function in disease and how this can be utilised to benefit human health. I will use structural biology to visualise sulfatases; this will allow molecules to be designed that can alter their function and thus prevent them eliciting the aforementioned disease states.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL