title: Mannose phosphorylation in health and disease.
abstract: Lysosomal hydrolases catalyze the degradation of a variety of macromolecules including proteins, carbohydrates, nucleic acids and lipids. The biogenesis of lysosomes or lysosome-related organelles requires a continuous substitution of soluble acid hydrolases and lysosomal membrane proteins. The targeting of lysosomal hydrolases depends on mannose 6-phosphate residues (M6P) that are recognized by specific receptors mediating their transport to an endosomal/prelysosomal compartment. The key role in the formation of M6P residues plays the GlcNAc-1-phosphotransferase localized in the Golgi apparatus. Two genes have been identified recently encoding the type III alpha/beta-subunit precursor membrane protein and the soluble gamma-subunit of GlcNAc-1-phosphotransferase. Mutations in these genes result in two severe diseases, mucolipidosis type II (MLII) and III (MLIII), biochemically characterized by the missorting of multiple lysosomal hydrolases due to impaired formation of the M6P recognition marker, and general lysosomal dysfunction. This review gives an update on structural properties, localization and functions of the GlcNAc-1-phosphotransferase subunits and improvements of pre- and postnatal diagnosis of ML patients. Further, the generation of recombinant single-chain antibody fragments against M6P residues and of new mouse models of MLII and MLIII will have considerable impact to provide deeper insight into the cell biology of lysosomal dysfunctions and the pathomechanisms underlying these lysosomal disorders.
authors: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Research Campus, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Katrin
authors: K
authors: Kollmann
authors: Sandra
authors: S
authors: Pohl
authors: Katrin
authors: K
authors: Marschner
authors: Marisa
authors: M
authors: Encarnação
authors: Imme
authors: I
authors: Sakwa
authors: Stephan
authors: S
authors: Tiede
authors: Ben J
authors: BJ
authors: Poorthuis
authors: Torben
authors: T
authors: Lübke
authors: Sven
authors: S
authors: Müller-Loennies
authors: Stephan
authors: S
authors: Storch
authors: Thomas
authors: T
authors: Braulke
mesh_terms: D000818:Animals; D004194:Disease; D006262:Health; D006801:Humans; D008358:Mannose / Q000378:metabolism*; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D017855:Transferases (Other Substituted Phosphate Groups) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); D008358:Mannose