Longevity & AgingBrain sugar branching by GnT-IX sets up keratan sulfate production on O-mannose glycans
O-mannose glycans make up roughly a third of O-glycans in the brain. A brain-specific enzyme, GnT-IX (MGAT5B), adds a branch to them, and this branching has been linked to demyelination and glioma. Until now it was unclear how GnT-IX recognizes O-mannose rather than N-glycan substrates, and what branching does downstream. Using structural modeling against its relative GnT-V, mutagenesis, and in vitro enzyme assays, the authors found that a single arginine (R304) drives GnT-IX's preference for O-mannose glycans. In GnT-IX knockout mouse brain, keratan sulfate on O-mannose glycans was significantly reduced. Enzyme assays showed that keratan sulfate-building enzymes B4GALT1, B4GALT4, and CHST1 work better on branched than linear O-mannose glycans. Branching therefore appears to provide a scaffold for efficient glycan elongation. These are preclinical, mechanistic findings.
