Summary: Phosphoric acid esters of mannose.

Top Publications

  1. Boonen M, Vogel P, Platt K, Dahms N, Kornfeld S. Mice lacking mannose 6-phosphate uncovering enzyme activity have a milder phenotype than mice deficient for N-acetylglucosamine-1-phosphotransferase activity. Mol Biol Cell. 2009;20:4381-9 pubmed publisher
  2. Kreiling J, Byrd J, MacDonald R. Domain interactions of the mannose 6-phosphate/insulin-like growth factor II receptor. J Biol Chem. 2005;280:21067-77 pubmed
    ..We conclude that there is no finite M6P/IGF2R dimerization domain, but rather that interactions between dimer partners occur all along the extracytoplasmic region of the receptor. ..
  3. Ludwig T, Eggenschwiler J, Fisher P, D Ercole A, Davenport M, Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev Biol. 1996;177:517-35 pubmed
  4. Gao N, Shang J, Huynh D, Manthati V, Arias C, Harding H, et al. Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides. Mol Biol Cell. 2011;22:2994-3009 pubmed publisher
    ..Apparently conserved throughout evolution, LLO destruction may be a response to a variety of environmental stresses. ..
  5. Gonzalo T, Beljaars L, van de Bovenkamp M, Temming K, van Loenen A, Reker Smit C, et al. Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther. 2007;321:856-65 pubmed
    ..We therefore conclude that delivery of a PDGF-kinase inhibitor to HSC is a promising technology to attenuate liver fibrogenesis. ..
  6. Temming K, Fretz M, Kok R. Organ- and cell-type specific delivery of kinase inhibitors: a novel approach in the development of targeted drugs. Curr Mol Pharmacol. 2008;1:1-12 pubmed
    ..Finally, we review the pharmacological efficacy of the cellular targeted drug conjugates in experimental animal models, especially in renal and liver fibrosis models. ..
  7. Zhou Q, Kyazike J, Edmunds T, Higgins E. Mannose 6-phosphate quantitation in glycoproteins using high-pH anion-exchange chromatography with pulsed amperometric detection. Anal Biochem. 2002;306:163-70 pubmed
    ..The assay was also linear when measuring mannose 6-phosphate on electroblots. Therefore, this assay has been shown to be specific, sensitive, and reproducible. ..
  8. Bernon C, Carre Y, Kuokkanen E, Slomianny M, Mir A, Krzewinski F, et al. Overexpression of Man2C1 leads to protein underglycosylation and upregulation of endoplasmic reticulum-associated degradation pathway. Glycobiology. 2011;21:363-75 pubmed publisher
    ..Disturbance in these pathways interferes with protein glycosylation and upregulated ERAD. Our findings support a new concept that regulation of Man2C1 expression is essential for maintaining efficient protein N-glycosylation. ..
  9. Boonen M, van Meel E, Oorschot V, Klumperman J, Kornfeld S. Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes. Mol Biol Cell. 2011;22:1135-47 pubmed publisher
    ..Taken together, our results provide new insights into the mechanisms of the tissue-specific abnormalities seen in mucolipidosis type II...

More Information


  1. van Meel E, Boonen M, Zhao H, Oorschot V, Ross F, Kornfeld S, et al. Disruption of the Man-6-P targeting pathway in mice impairs osteoclast secretory lysosome biogenesis. Traffic. 2011;12:912-24 pubmed publisher
    ..However, cathepsin D targeting was intact, showing that osteoclasts have a Man-6-P-independent pathway for selected acid hydrolases. ..
  2. Nielsen R, Courtoy P, Jacobsen C, Dom G, Lima W, Jadot M, et al. Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci U S A. 2007;104:5407-12 pubmed
    ..These results also extend the significance of megalin in PCT and have several physiopathological and clinical implications. ..
  3. Beljaars L, Molema G, Weert B, Bonnema H, Olinga P, Groothuis G, et al. Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells. Hepatology. 1999;29:1486-93 pubmed
    ..This technology may create new opportunities for the pharmacological intervention of liver fibrosis. ..
  4. Dahms N, Olson L, KIM J. Strategies for carbohydrate recognition by the mannose 6-phosphate receptors. Glycobiology. 2008;18:664-78 pubmed publisher
    ..Recent structural studies have given us a clearer view of how these two receptors use related, but yet distinct, approaches in the recognition of phosphomannosyl residues. ..
  5. Pirard M, Collet J, Matthijs G, Van Schaftingen E. Comparison of PMM1 with the phosphomannomutases expressed in rat liver and in human cells. FEBS Lett. 1997;411:251-4 pubmed
    ..Phosphomannomutases belong to a novel mutase family in which the active residue is a phosphoaspartyl or a phosphoglutamyl. ..
  6. Lee S, Nathans D. Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. J Biol Chem. 1988;263:3521-7 pubmed
  7. Gao N, Shang J, Lehrman M. Analysis of glycosylation in CDG-Ia fibroblasts by fluorophore-assisted carbohydrate electrophoresis: implications for extracellular glucose and intracellular mannose 6-phosphate. J Biol Chem. 2005;280:17901-9 pubmed
    ..The possibilities that M6P may accumulate in hepatocytes and that M6P-stimulated LLO cleavage may account for both hypoglycosylation and the clinical failure of dietary mannose therapy with CDG-Ia patients are discussed. ..
  8. DeRossi C, Bode L, Eklund E, Zhang F, Davis J, Westphal V, et al. Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality. J Biol Chem. 2006;281:5916-27 pubmed
    ..5 Mpi(-/-) embryos where Man-6-P increased more than 10 times, and ATP decreased by 50% compared with Mpi(+/+) littermates. Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles. ..
  9. Adrian J, Poelstra K, Scherphof G, Molema G, Meijer D, Reker Smit C, et al. Interaction of targeted liposomes with primary cultured hepatic stellate cells: Involvement of multiple receptor systems. J Hepatol. 2006;44:560-7 pubmed
    ..Both the mannose 6-phosphate receptor and the scavenger receptors are involved in the uptake process. M6P-HSA liposomes are potential drug carriers to HSC in the fibrotic liver. ..
  10. Olson L, Peterson F, Castonguay A, Bohnsack R, Kudo M, Gotschall R, et al. Structural basis for recognition of phosphodiester-containing lysosomal enzymes by the cation-independent mannose 6-phosphate receptor. Proc Natl Acad Sci U S A. 2010;107:12493-8 pubmed publisher
    ..These results show the mechanism by which the CI-MPR recognizes Man-P-GlcNAc-containing ligands and provides new avenues to investigate the role of phosphodiester-containing lysosomal enzymes in the biogenesis of lysosomes. ..
  11. Mitra S, Cui J, Robbins P, Samuelson J. A deeply divergent phosphoglucomutase (PGM) of Giardia lamblia has both PGM and phosphomannomutase activities. Glycobiology. 2010;20:1233-40 pubmed publisher
    ..Recombinant Gl-PGM1 has PGM activity only, whereas Gl-PGM2 has both PGM and PMM activities. We conclude that Gl-PGM1 behaves as a conventional eukaryotic PGM, while Gl-PGM2 is a novel eukaryotic PGM that also has PMM activity...
  12. Zhou M, Ma Z, Sly W. Cloning and expression of the cDNA of chicken cation-independent mannose-6-phosphate receptor. Proc Natl Acad Sci U S A. 1995;92:9762-6 pubmed
    ..Expression of the functional chicken CI-MPR in mice lacking the mammalian CI-MPR should clarify the controversy over the physiological role of the IGF-II-binding site in mammalian CI-MPR homologs. ..
  13. Sharma V, Ichikawa M, He P, Scott D, Bravo Y, Dahl R, et al. Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts. J Biol Chem. 2011;286:39431-8 pubmed publisher
    ..Finally, we show that MLS0315771 increases mannose metabolic flux toward glycosylation in zebrafish embryos. ..
  14. Sleat D, Della Valle M, Zheng H, Moore D, Lobel P. The mannose 6-phosphate glycoprotein proteome. J Proteome Res. 2008;7:3010-21 pubmed publisher
    ..This approach provides a list of candidate lysosomal proteins and also provides insights into the relative distribution of Man6-P glycoproteins. ..
  15. Reczek D, Schwake M, Schröder J, Hughes H, Blanz J, Jin X, et al. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007;131:770-83 pubmed
    ..These data support a role for LIMP-2 as the mannose-6-phosphate-independent trafficking receptor for beta-glucocerebrosidase. ..
  16. Flanagan Steet H, Sias C, Steet R. Altered chondrocyte differentiation and extracellular matrix homeostasis in a zebrafish model for mucolipidosis II. Am J Pathol. 2009;175:2063-75 pubmed publisher
    ..These findings highlight the potential of the zebrafish system in studying lysosomal disease pathogenesis...
  17. Higashidani A, Bode L, Nishikawa A, Freeze H. Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosylation-deficient human fibroblasts. Mol Genet Metab. 2009;96:268-72 pubmed publisher
    ..These results make it very unlikely that exogenous mannose could impair N-glycosylation in glycosylation-deficient CDG patients. ..
  18. Greupink R, Bakker H, van Goor H, de Borst M, Beljaars L, Poelstra K. Mannose-6-phosphate/insulin-Like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells. Pharm Res. 2006;23:1827-34 pubmed
    ..M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA. ..
  19. Freeze H. Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients. Biochim Biophys Acta. 2009;1792:835-40 pubmed publisher
    ..Glycosylation-deficient cell and animal models are needed to determine which individual or combined approaches improve glycosylation and may be suitable for preclinical evaluation. ..
  20. Beljaars L, Olinga P, Molema G, De Bleser P, Geerts A, Groothuis G, et al. Characteristics of the hepatic stellate cell-selective carrier mannose 6-phosphate modified albumin (M6P(28)-HSA). Liver. 2001;21:320-8 pubmed
    ..This may have implications for the design of new strategies for the treatment of liver fibrosis. ..
  21. Lobel P, Dahms N, Breitmeyer J, Chirgwin J, Kornfeld S. Cloning of the bovine 215-kDa cation-independent mannose 6-phosphate receptor. Proc Natl Acad Sci U S A. 1987;84:2233-7 pubmed
    ..Each repeat contains a highly conserved 13-amino acid unit bordered by cysteine residues that may be functionally important. ..
  22. Greupink R, Bakker H, Reker Smit C, van Loenen Weemaes A, Kok R, Meijer D, et al. Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell. J Hepatol. 2005;43:884-92 pubmed
    ..This study shows that targeted delivery of MPA to HSC results in a decrease in HSC activation, making it the first drug that is successfully delivered to this cell type. ..
  23. Journet A, Chapel A, Kieffer S, Louwagie M, Luche S, Garin J. Towards a human repertoire of monocytic lysosomal proteins. Electrophoresis. 2000;21:3411-9 pubmed
  24. Ye Z, Cheng K, Guntaka R, Mahato R. Targeted delivery of a triplex-forming oligonucleotide to hepatic stellate cells. Biochemistry. 2005;44:4466-76 pubmed
    ..Therefore, this TFO conjugate may be used for the treatment of liver fibrosis. ..
  25. Sharma V, Nayak J, DeRossi C, Charbono A, Ichikawa M, Ng B, et al. Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. FASEB J. 2014;28:1854-69 pubmed publisher
  26. Ye Z, Cheng K, Guntaka R, Mahato R. Receptor-mediated hepatic uptake of M6P-BSA-conjugated triplex-forming oligonucleotides in rats. Bioconjug Chem. 2006;17:823-30 pubmed
    ..Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis. ..
  27. Collins B, Skinner C, Watson P, Seaman M, Owen D. Vps29 has a phosphoesterase fold that acts as a protein interaction scaffold for retromer assembly. Nat Struct Mol Biol. 2005;12:594-602 pubmed
  28. Cury G, Matte U, Artigalas O, Alegra T, Velho R, Sperb F, et al. Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene. Gene. 2013;524:59-64 pubmed publisher
    ..Further analyses will be conducted on patients in whom both pathogenic mutations have not been found in this study. ..
  29. Angunawela R, Marshall J. Inhibition of transforming growth factor-beta1 and its effects on human corneal fibroblasts by mannose-6-phosphate Potential for preventing haze after refractive surgery. J Cataract Refract Surg. 2010;36:121-6 pubmed publisher
    ..Neither author has a financial or proprietary interest in any material or method mentioned. ..
  30. Dunder U, Mononen I. Human leukocyte glycosylasparaginase: cell-to-cell transfer and properties in correction of aspartylglycosaminuria. FEBS Lett. 2001;499:77-81 pubmed
    ..The combined evidence indicates that cell-to-cell transfer of GA plays a main role in enzyme replacement therapy of AGU by normal lymphocytes. ..
  31. Lemansky P, Hasilik A. Chondroitin sulfate is involved in lysosomal transport of lysozyme in U937 cells. J Cell Sci. 2001;114:345-52 pubmed
    ..Our results suggest that the proteoglycan is involved in lysosomal targeting of lysozyme in U937 cells. ..
  32. Ioannou Y, Bishop D, Desnick R. Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion. J Cell Biol. 1992;119:1137-50 pubmed
    ..A significant proportion of these enzyme aggregates are unable to bind the M6PR and are selectively secreted via the constitutive secretory pathway, while endogenous lysosomal enzymes bind the M6PRs and are transported to lysosomes. ..
  33. Laube F. Mannose-6-phosphate/insulin-like growth factor-II receptor in human melanoma cells: effect of ligands and antibodies on the receptor expression. Anticancer Res. 2009;29:1383-8 pubmed
    ..Up-regulation of the tumour suppressor M6P/IGF-II receptor might represent an approach for anticancer therapy. In addition, results support recent data on the receptor's capability of signal transduction. ..
  34. Coutinho M, Prata M, Alves S. Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol Genet Metab. 2012;105:542-50 pubmed publisher
    ..Impairments in this pathway will also be addressed, highlighting the lysosomal storage disorders associated to GlcNAc-1-phosphotransferase loss of function: mucolipidosis type II and III. ..
  35. Szebenyi G, Rotwein P. Differential regulation of mannose 6-phosphate receptors and their ligands during the myogenic development of C2 cells. J Biol Chem. 1991;266:5534-9 pubmed
    ..The differential regulation of the two mannose 6-phosphate receptors during muscle differentiation suggests that they may serve distinct functions in development. ..
  36. Hazen K, Singleton D, Masuoka J. Influence of outer region mannosylphosphorylation on N-glycan formation by Candida albicans: normal acid-stable N-glycan formation requires acid-labile mannosylphosphate addition. Glycobiology. 2007;17:1052-60 pubmed
    ..albicans are interdependent events and occur concurrently, rather than sequentially. ..
  37. Pavelic J, Radakovic B, Pavelic K. Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma. Gynecol Oncol. 2007;105:727-35 pubmed
  38. Bates S, Morrow E, Zhang A, Pham H, Longaker M, Chang J. Mannose-6-phosphate, an inhibitor of transforming growth factor-beta, improves range of motion after flexor tendon repair. J Bone Joint Surg Am. 2006;88:2465-72 pubmed
    ..This finding correlated with our in vivo finding that a single intraoperative dose of mannose-6-phosphate improved the postoperative range of motion. ..
  39. Corbacho I, Olivero I, Hernández L. A genome-wide screen for Saccharomyces cerevisiae nonessential genes involved in mannosyl phosphate transfer to mannoprotein-linked oligosaccharides. Fungal Genet Biol. 2005;42:773-90 pubmed
    ..We have assigned an LDB name to four uncharacterized ORFs identified in this study: YCL005W, LDB16; YDL146W, LDB17; YLL049W, LDB18; and YOR322C, LDB19. ..
  40. Viswanathan K, Narang S, Hinderlich S, Lee Y, Betenbaugh M. Engineering intracellular CMP-sialic acid metabolism into insect cells and methods to enhance its generation. Biochemistry. 2005;44:7526-34 pubmed
  41. Hirosako K, Imasato H, Hirota Y, Kuronita T, Masuyama N, Nishioka M, et al. 3-Methyladenine specifically inhibits retrograde transport of cation-independent mannose 6-phosphate/insulin-like growth factor II receptor from the early endosome to the TGN. Biochem Biophys Res Commun. 2004;316:845-52 pubmed
    ..The results suggest that the effect of 3-MA is restricted to the retrieval of MPR300 from early/recycling endosomes. ..
  42. Sacchetti S, Bartolucci S, Rossi M, Cannio R. Identification of a GDP-mannose pyrophosphorylase gene from Sulfolobus solfataricus. Gene. 2004;332:149-57 pubmed
    ..The enzyme was definitively identified by demonstrating its capability to catalyze also the reverse reaction of pyrophosphorolysis and, most interestingly, its high specificity for synthesizing GDP-mannose. ..
  43. Hartman M, Kreiling J, Byrd J, MacDonald R. High-affinity ligand binding by wild-type/mutant heteromeric complexes of the mannose 6-phosphate/insulin-like growth factor II receptor. FEBS J. 2009;276:1915-29 pubmed publisher
    ..Although wild-type/mutant hetero-oligomers form readily when mixed, it appears that multivalent Man-6-P ligands bind preferentially to wild-type sites, possibly by cross-bridging receptors within clusters of immobilized receptors. ..
  44. Taguchi Y, Saburi W, Imai R, Mori H. Evaluation of acceptor selectivity of Lactococcus lactis ssp. lactis trehalose 6-phosphate phosphorylase in the reverse phosphorolysis and synthesis of a new sugar phosphate. Biosci Biotechnol Biochem. 2017;81:1512-1519 pubmed publisher
    ..Suitable acceptor substrates were Glc6P, and, at a low level, d-mannose 6-phosphate (Man6P). From ?-Glc1P and Man6P, a novel sugar phosphate, ?-d-Glcp-(1?1)-?-d-Manp6P, was synthesized with 51% yield. ..
  45. Boose J, Tifft C, Proia R, Myerowitz R. Synthesis of a human lysosomal enzyme, beta-hexosaminidase B, using the baculovirus expression system. Protein Expr Purif. 1990;1:111-20 pubmed
    ..Generous amounts of easily obtained, easily purified, and properly folded beta-hexosaminidase B will facilitate physical structural analysis of the enzyme. ..
  46. Sleat D, Sun P, Wiseman J, Huang L, El Banna M, Zheng H, et al. Extending the mannose 6-phosphate glycoproteome by high resolution/accuracy mass spectrometry analysis of control and acid phosphatase 5-deficient mice. Mol Cell Proteomics. 2013;12:1806-17 pubmed publisher
  47. Rashid N, Kanai T, Atomi H, Imanaka T. Among multiple phosphomannomutase gene orthologues, only one gene encodes a protein with phosphoglucomutase and phosphomannomutase activities in Thermococcus kodakaraensis. J Bacteriol. 2004;186:6070-6 pubmed publisher
    ..Our results clearly indicate that, among the four PMM gene orthologues in T. kodakaraensis, only one gene, TK1108, actually encodes a protein with PGM and PMM activities...
  48. Sun Q, Li J, Wang C, Huang X, Huang H, Du D, et al. Overexpression of mouse GlcNAc-1-phosphotransferase-gamma subunit in cells induced an I-cell-like phenotype of mucolipidosis. Gene. 2005;347:55-64 pubmed
  49. Muschol N, Matzner U, Tiede S, Gieselmann V, Ullrich K, Braulke T. Secretion of phosphomannosyl-deficient arylsulphatase A and cathepsin D from isolated human macrophages. Biochem J. 2002;368:845-53 pubmed
    ..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. ..
  50. Han J, Gu Y, Li G, Jia W, Luo M. [The effect of mannose-6-phosphate on adipocyte differentiation and its underlying molecular mechanism]. Zhonghua Nei Ke Za Zhi. 2010;49:785-8 pubmed
    ..9% at 10.0 mmol/L compared with the control group (P < 0.05). M6P inhibits the terminal differentiation of adipocyte, which may be associated with its effect of blocking CTSK activity by competitive binding with M6PR. ..
  51. Hanafusa T, Yumoto Y, Nouso K, Nakatsukasa H, Onishi T, Fujikawa T, et al. Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett. 2002;176:149-58 pubmed
    ..As IGFBP-3 functions like a tumor suppressor gene, it may be used as a therapeutic target for HCC. ..
  52. Qian M, Sleat D, Zheng H, Moore D, Lobel P. Proteomics analysis of serum from mutant mice reveals lysosomal proteins selectively transported by each of the two mannose 6-phosphate receptors. Mol Cell Proteomics. 2008;7:58-70 pubmed
    ..This study provides a comparison of different quantitative mass spectrometric approaches and provides the first report of proteins whose cellular targeting appears to be MPR-selective under physiological conditions. ..
  53. Zhu Y, Jiang J, Gumlaw N, Zhang J, Bercury S, Ziegler R, et al. Glycoengineered acid alpha-glucosidase with improved efficacy at correcting the metabolic aberrations and motor function deficits in a mouse model of Pompe disease. Mol Ther. 2009;17:954-63 pubmed publisher
    ..These findings lend support to early therapeutic intervention with a targeted enzyme as important considerations in the management of Pompe disease. ..