ppGalNAcTs

ppGalNAcTs, or polypeptide N-acetylgalactosaminyltransferases, are a family of enzymes that initiate mucin-type O-glycosylation by transferring N-acetylgalactosamine from UDP-GalNAc to serine or threonine residues on polypeptides, forming the Tn antigen. The activity of ppGalNAc-Ts shapes the initial O-glycosylation pattern of many glycoproteins, notably mucins, and influences protein folding, stability, and interactions.

Most ppGalNAc-Ts are type II transmembrane proteins resident in the Golgi apparatus. They possess a short cytosolic tail, a single transmembrane domain, and a luminal region that contains a catalytic glycosyltransferase domain (GT-A fold) and, in many members, a C-terminal lectin-like domain that can recognize GalNAc-containing structures and contribute to substrate selection and processivity. The family is large and diverse, with multiple isoforms in vertebrates (for example, humans encode GALNT1 through GALNT14), each with distinct tissue distribution and substrate preferences. This variability allows combinatorial patterns of O-glycosylation across different cell types and developmental stages.

Functionally, ppGalNAc-Ts can act as initiators by attaching GalNAc to Ser/Thr residues and, in some cases, also participate in extending existing O-glycans in the Golgi. The resulting GalNAc-Ser/Thr structures can be elaborated by other glycosyltransferases to form core O-glycan structures.

Clinical and research relevance includes associations between GALNT gene function and congenital disorders of glycosylation, cancer-related glycosylation changes, and metabolic traits such as HDL cholesterol levels. Structural and biochemical studies aid in understanding substrate specificity and regulation of this enzyme family.