Decoding the complex substrate specificities of GalNAc-Ts

GalNAc-Ts are a large family of glycosyltransferases that regulate numerous cellular processes by initiating the post-translational modification mucin-type O-glycosylation. Disruptions in GalNAc-T expression and function are associated with congenital diseases, metabolic disorders, and cancer. The substrates and acceptor sites affected by the inactivation or over-activation of each specific family member are often not known due to acceptor site and substrate redundancies among the isoenzymes that are present within a cell type. However, substantial progress has been made in disentangling the enzyme-substrate conundrum by showing that each isoenzyme follows a unique set of substrate recognition rules. This review summarizes biochemical and structural findings that have advanced our understanding of the distinct substrate specificities of individual GalNAc-Ts.