title: Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology.
abstract: Lysosomal enzymes sialidase (alpha-neuraminidase), beta-galactosidase, and N-acetylaminogalacto-6-sulfate sulfatase are involved in the catabolism of glycolipids, glycoproteins, and oligosaccharides. Their functional activity in the cell depends on their association in a multienzyme complex with lysosomal carboxypeptidase, cathepsin A. We review the data suggesting that the integrity of the complex plays a crucial role at different stages of biogenesis of lysosomal enzymes, including intracellular sorting and proteolytic processing of their precursors. The complex plays a protective role for all components, extending their half-life in the lysosome from several hours to several days; and for sialidase, the association with cathepsin A is also necessary for the expression of enzymatic activity. The disintegration of the complex due to genetic mutations in its components results in their functional deficiency and causes severe metabolic disorders: sialidosis (mutations in sialidase), GM1-gangliosidosis and Morquio disease type B (mutations in beta-galactosidase), galactosialidosis (mutations in cathepsin A), and Morquio disease type A (mutations in N-acetylaminogalacto-6-sulfate sulfatase). The genetic, biochemical, and direct structural studies described here clarify the molecular pathogenic mechanisms of these disorders and suggest new diagnostic tools.
authors.affiliation: Servive de Génétique Médicale, Hôpital Sainte-Justine and Département de Pédiatrie, Faculté de Médicine, Université de Montréal, Canada.
authors.forename: A V
authors.initials: AV
authors.lastname: Pshezhetsky
authors.forename: M
authors.initials: M
authors.lastname: Ashmarina
mesh_terms: D002268:Carboxypeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D043422:Carboxypeptidases A; D002462:Cell Membrane / Q000201:enzymology; D002811:Chondroitinsulfatases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology*; D008958:Models, Molecular; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics; D009085:Mucopolysaccharidosis IV / Q000201:enzymology / Q000235:genetics; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D009439:Neuraminidase / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D001616:beta-Galactosidase / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: D009097:Multienzyme Complexes; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D002811:Chondroitinsulfatases; C102295:GALNS protein, human; D009439:Neuraminidase; D001616:beta-Galactosidase; D002268:Carboxypeptidases; D043422:Carboxypeptidases A