Disease relevance of Mannose 6-phosphate

• Mucolipidosis II (ML II) is a fatal lysosomal storage disorder resulting from defects in the multimeric GlcNAc-1-phosphotransferase responsible for the initial step in the generation of the mannose 6-phosphate (M6P) recognition marker [1].
• We conclude that in breast cancer cells, even though procath-D interacts intracellularly and extracellarly with prosaposin, it is endocytosed independent of prosaposin by a receptor different from the M6P receptors and the LRP [2].
• We compared two recombinant alpha-galactosidases developed for enzyme replacement therapy for Fabry disease, agalsidase alfa and agalsidase beta, as to specific alpha-galactosidase activity, stability in plasma, mannose 6-phosphate (M6P) residue content, and effects on cultured human Fabry fibroblasts and Fabry mice [3].

High impact information on Mannose 6-phosphate

• M6P residues on oligosaccharides of newly synthesized lysosomal enzymes are essential for efficient receptor-mediated transport to lysosomes [1].
• We have previously reported that lymphocyte attachment to PN HEV is selectively inhibited by mannose-6-phosphate (M6P) and related carbohydrates (Stoolman, L. M., T. S. Tenforde, and S. D. Rosen, 1984, J. Cell Biol., 99:1535-1540) [4].
• The Tat motif allowed for mannose-6-phosphate (M6P) independent uptake in vitro and significantly increased the distribution of beta-glucuronidase secreted from transduced cells after intravenous or direct brain injection in mice of recombinant vectors [5].
• Collectively, these data suggest that different carbohydrate structures are involved in the entry of lymphocytes into different lymphoid organs, with mannose recognition playing an important role in splenic entry and recognition of M6P-like structures controlling lymph node entry [6].
• In this study, we evaluate the potential of liver-directed gene therapy, that is, programming of murine hepatocytes to secrete the enzyme with mannose 6-phosphate (M6P), which can be taken up by distant cells [7].

Biological context of Mannose 6-phosphate

• The cell surface binding, endocytosis, and lysosomal routing of procathepsin D (procath-D) in cancer cells are mostly independent of the mannose-6-phosphate (M6P) receptors [2].

Anatomical context of Mannose 6-phosphate

• Moreover, RAP (receptor-associated protein), a ligand inhibiting LRP-mediated endocytosis, prevented internalization of prosaposin in 49-F rat fibroblasts, but did not affect procath-D M6P-independent internalization in MDA-MB231 cells [2].
• These data indicated that lysosomal enzymes secreted by human macrophages or a mouse microglial cell line cannot be endocytosed by brain cells due to the failure to equip newly synthesized lysosomal enzymes with the M6P recognition marker efficiently [8].
• Co-culturing of metabolically labelled macrophages with ASA-deficient glial cells did not result in an M6P-dependent transfer of ASA or CTSD between these two cell types [8].
• The data suggest that other mechanisms than the proposed M6P-dependent secretion/recapture of lysosomal enzymes might be responsible for therapeutic effects of bone marrow transplantation in the brain [8].
• Lymphocyte binding to lymph node high endothelial venules (HEV) has been shown to be inhibited by mannose-6-phosphate (M6P) and to kidney peritubular capillaries by mannose-1-phosphate (M1P) [9].

Associations of Mannose 6-phosphate with other chemical compounds

• In contrast, it was found that mannose-and M6P-containing structures, unlike sulfated polysaccharides such as fucoidan, did not affect the subsequent positioning of lymphocytes within lymphoid organs [6].
• In contrast, mannose 6 phosphate (M6P) did not alter RA or IGF-II actions [10].

Gene context of Mannose 6-phosphate

• In fibroblasts, we confirmed that the endocytosis of these two proteins was different since it was generally mediated by the M6P receptors for procath-D and mostly by LRP (LDL receptor-related protein) for prosaposin [2].
• The effectiveness of these two phosphomonosaccharides varied depending on the source of the enzyme: ileal beta-NAG-ligatin complexes showed a four-fold preferential dissociation with Man6P; macrophage complexes showed a 160-fold preferential dissociation with Glc 1P [11].
• Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor [12].
• Mono- and bivalent ligands bearing mannose 6-phosphate (M6P) surrogates: targeting the M6P/insulin-like growth factor II receptor [13].
• Our data indicate that the transfected as well as the infected cells produce a large amount of the IDS enzyme, which is efficiently endocytosed into neuronal and glial cells through the mannose 6-phosphate (M6P) receptor system [14].

Analytical, diagnostic and therapeutic context of Mannose 6-phosphate

• The solubilized beta-NAG bound to ligatin in vitro as demonstrated by affinity chromatography using the immobilized receptor. beta-N-Acetyl D-glucosaminidase-ligatin complexes were dissociated by low concentrations of mannose 6-phosphate (Man6P) and/or glucose 1-phosphate (Glc 1P) [11].

References