Understanding glycosylation: Regulation through the metabolic flux of precursor pathways

Glycosylation is how proteins and lipids are modified with complex carbohydrates known as glycans. The posttranslational modification of proteins with glycans is not a template-driven process in the same way as genetic transcription or protein translation. Glycosylation is instead dynamically regulated by metabolic flux. This metabolic flux is determined by the concentrations and activities of the glycotransferase enzymes, which synthesise glycans, the metabolites that act as their precursors and transporter proteins. This review provides an overview of the metabolic pathways underlying glycan synthesis. Pathological dysregulation of glycosylation, particularly increased glycosylation occurring during inflammation, is also elucidated. The resulting inflammatory hyperglycosylation acts as a glycosignature of disease, and we report on the changes in the metabolic pathways which feed into glycan synthesis, revealing alterations to key enzymes. Finally, we examine studies in developing metabolic inhibitors targeting these critical enzymes. These results provide the tools for researchers investigating the role of glycan metabolism in inflammation and have helped to identify promising glycotherapeutic approaches to inflammation. This publication has emanated from research supported by a research grant from Science Foundation Ireland (SFI), co-funded under the European Regional Development Fund through Grant number 13/ RC/2073_P2, by the PREMUROSA project, which is funded by the European Union’s Horizon 2020 Programme (H2020-MSCA-ITN-2019) under the Marie Skłodowska-Curie Innovative Training Network Grant Agreement Number 860462 and by TBMED with funding from European Union’s Horizon 2020 programme (Grant Agreement No. 814439)