lysosomal multienzyme complex
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.
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.
Acidic glycosidases
Three acidic glycosidases: beta-galactosidase (beta-GAL, EC 3.2.1.23), alpha-neuraminidase (NEUR, sialidase, EC 3.2.1.18), N-acetylaminogalacto-6-sulfate sulfatase (GALNS, EC 3.1.6.4) and serine carboxypepidase cathepsin A (EC 3.4.16.1) form a functional high molecular weight complex in the lysosomes.
The major constituent of this complex is cathepsin A, the so-called "lysosomal protective protein" (PPCA).
By forming a multienzyme complex, it protects the glycosidases from rapid intralysosomal proteolysis, and it is also required for the intracellular sorting and proteolytic processing of their precursors. In man, a deficiency of cathepsin A leads to a combined deficiency of beta-GAL and NEUR activities, called "galactosialidosis".
Pathology
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
Morquio disease type B (mutations in beta-galactosidase)
galactosialidosis (mutations in cathepsin A)
Morquio disease type A (mutations in N-acetylaminogalacto-6-sulfate sulfatase)
Multiple mutations identified in the cathepsin A gene are the molecular basis of this lysosomal storage disease.
References
Ostrowska H, Krukowska K, Kalinowska J, Orlowska M, Lengiewicz I. Lysosomal high molecular weight multienzyme complex. Cell Mol Biol Lett. 2003;8(1):19-24. PMID: 12655352
Pshezhetsky AV, Ashmarina M. Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology. Prog Nucleic Acid Res Mol Biol. 2001;69:81-114. PMID: 11550799