Séminaire IBS : Atomistic and molecular studies of HS biosynthesis enzymes

Par Dr Liang Wu (Rosalind Franklin Institute, Harwell Campus, Didcot, UK)

Biological carbohydrates are some of the most complex molecules in life, reflecting a sophisticated repertoire of enzymes responsible for generating and modulating their structures. Seminal efforts in glycobiology have resolved structures of many individual carbohydrate processing enzymes, revealing how each catalyzes precise biochemical transformations. Despite this, we still have limited understanding of how many complex oligo/polysaccharides are formed, highlighting an overall lack of knowledge regarding multi-enzyme biosynthesis pathways.

We are interested in the biosynthesis and regulation of the complex polysaccharide heparan sulfate (HS), which is produced by all animal species, and plays vital roles in extracellular processes including cell adhesion, cytokine signalling, and host-pathogen engagement. Mammalian HS biosynthesis is mediated by a host of different enzyme activities within the Golgi (polymerases, sulfotransferases, epimerases etc). Several pathogenic bacteria have also evolved capability to produce HS mimetics, likely aiding their evasion from host immune responses. Because of the biological importance of HS, there is intense interest in understanding the enzymes responsible for its construction, and how they work to generate functional structures.

Here, I will present mechanistic studies of biosynthesis enzymes involved in HS polymerization and sulfation, revealing insights into atomistic reaction mechanism, and principles of enzyme-substrate regulation. Furthermore, recent efforts to understand contextual organization of enzymes within the Golgi by will be discussed, outlining current approaches and challenges towards cryo-electron imaging of intracellular environments. Collectively, our work provides further insights into the diverse substrate recognition, binding and processing mechanisms employed during enzymatic HS biosynthesis.

Hôte : Rebekka Wild (IBS/SAGAG)