Omannosyltransferase

O-mannosyltransferases are a family of glycosyltransferases that catalyze the transfer of a mannose residue from dolichyl-phosphate mannose (Dol-P-Man) to serine or threonine residues on polypeptides, initiating O-linked mannosylation in the secretory pathway. The reaction takes place in the endoplasmic reticulum, and the enzymes are typically integral membrane proteins with catalytic domains oriented toward the lumen.

In yeast and many fungi, PMTs operate as part of heteromeric complexes, with PMT1 and PMT2 forming one functional pair and PMT4 and PMT5 forming another, among other combinations. In mammals, the initial O-mannosylation step is mediated by Protein O-mannosyltransferases POMT1 and POMT2, which form a functional complex to mannosylate substrate proteins; additional homologs exist but POMT1/POMT2 are central in higher animals.

Substrates include a broad range of secreted and membrane proteins, notably α-dystroglycan. O-mannosylation influences protein folding, stability, trafficking, and interactions, and is essential for proper cell surface glycosylation patterns. The pathway is conserved across eukaryotes and is important for development and tissue integrity; disruption can affect multiple organ systems.

Clinical relevance centers on inherited defects in the mammalian O-mannosylation pathway, which cause congenital muscular dystrophies and neurodevelopmental disorders. Mutations in POMT1 or POMT2 lead to hypoglycosylation of substrates such as α-dystroglycan, contributing to diseases including Walker-Warburg syndrome and Muscle-Eye-Brain disease. Understanding O-mannosyltransferases illuminates both fundamental glycosylation biology and its role in human disease.