Mannose-6-phosphate
Mannose 6-phosphate
Chemical compound
Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase.
M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transport to lysosomes. The M6P tag is added to such proteins in the cis-Golgi apparatus. Specifically, in a reaction involving uridine diphosphate (UDP) and N-acetylglucosamine, the enzyme N-acetylglucosamine-1-phosphate transferase catalyzes the N-linked glycosylation of asparagine residues with M6P. Once appropriately marked with the M6P targeting signal, these proteins are moved to the trans-Golgi network. There, the M6P moiety is recognized and bound by mannose 6-phosphate receptor (MPR) proteins at pH 6.5–6.7.[1]
The M6P-tagged lysosomal enzymes are shipped to the late endosomes via vesicular transport.[1] Enzyme replacement therapy (ERT) for several lysosomal storage diseases relies on this pathway to efficiently direct synthetic enzymes to the lysosome where each can metabolize its particular substrate.[2] The pH in the late endosome can reach 6.0, which causes dissociation of M6P from its receptor.[1] Upon release, the enzymes are ferried to their final destination in the lysosomes.[1] The MPRs are packed into vesicles that bud off the late endosome and return to the trans-Golgi network.[1] In this way, the MPRs can be recycled.