mannose6fosfat

Mannose-6-phosphate is a phosphorylated derivative of the sugar mannose that serves as a key targeting tag for lysosomal enzymes in many eukaryotic cells. In its mature form, the phosphate group is attached at the 6-position of mannose residues on lysosomal hydrolases that are being prepared for transport to the lysosome. This label is essential for proper enzyme sorting and delivery within the endomembrane system.

Biosynthesis and maturation occur in the Golgi apparatus. The enzyme N-acetylglucosamine-1-phosphotransferase transfers a phospho-N-acetylglucosamine group to specific lysosomal enzyme glycans. A subsequent uncovering enzyme removes the GlcNAc moiety, leaving the mannose-6-phosphate tag exposed on the enzyme. Not all lysosomal enzymes acquire M6P, and the efficiency of tagging can influence lysosomal enzyme levels.

Mannose-6-phosphate directs lysosomal enzymes to the lysosome through interaction with mannose-6-phosphate receptors. There are cation-dependent and cation-independent M6P receptors (CD-MPR and CI-MPR). The receptors recognize M6P-bearing enzymes in the Golgi or at the cell surface and route them to late endosomes, where the acidic environment promotes release of the enzyme for lysosomal function. The CI-MPR/IGF2R receptor has additional roles in growth factor signaling beyond lysosomal trafficking.

Clinical relevance includes the lysosomal storage disorder I-cell disease (mucolipidosis II), caused by deficiency of the phosphotransferase that initiates M6P tagging. Resulting failure to tag enzymes leads to their misdirection and elevated extracellular lysosomal enzymes. M6P tagging is also exploited in enzyme replacement therapies to enhance delivery of therapeutic lysosomal enzymes to lysosomes.