Mannose6phosphate

Mannose-6-phosphate (M6P) is a phosphorylated form of the sugar mannose that serves as a key tag on lysosomal enzymes. In mammalian cells, most lysosomal hydrolases acquire the M6P marker in the Golgi apparatus, directing them to lysosomes where they function in macromolecule degradation.

Biosynthesis and tagging occur in the secretory pathway. A specific enzyme, UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, transfers a GlcNAc-1-phosphate group to a mannose residue on the lysosomal enzyme's N-linked glycan. A subsequent uncovering enzyme removes the GlcNAc moiety, leaving a single phosphate on the C6 hydroxyl of the mannose, i.e., the mannose-6-phosphate tag. This tagging is essential for recognition by mannose-6-phosphate receptors.

M6P plays a central role in lysosomal enzyme targeting and trafficking. The M6P tag is recognized by mannose-6-phosphate receptors (MPRs) in the trans-Golgi network and on endosomal membranes. The receptor–enzyme complex is sorted into clathrin-coated vesicles and delivered to lysosomes, ensuring enzymes reach their intended compartment. The receptors can also mediate uptake of secreted M6P-tagged enzymes from the extracellular space if cells possess corresponding receptors.

Clinical significance is notable when the tagging pathway is defective. Deficiency of GlcNAc-1-phosphotransferase causes mucolipidosis II (I-cell disease), characterized by mis-sorted lysosomal enzymes that are secreted rather than delivered to lysosomes, leading to widespread cellular dysfunction. Enzyme replacement therapies exploit the M6P–receptor pathway to deliver functional lysosomal enzymes to patient cells.