[Lysosomal glycosidases and glycoproteinoses]

Area of Science:

• Biochemistry
• Glycobiology
• Cell Biology

Context:

• Advancements in chemical, physical, and enzymatic methods have enabled detailed structural determination of glycoprotein glycans.
• Classification of glycans into "structural families" provides a framework for understanding their biological roles.
• Lysosomal storage diseases are characterized by deficiencies in specific lysosomal glycosidases, leading to the accumulation of undegraded substrates.

Purpose:

• To demonstrate that accumulating oligosaccharides and glycoasparagines in lysosomal storage diseases originate from incompletely catabolized glycoprotein glycans.
• To propose a comprehensive scheme for both normal and pathological glycoprotein catabolism.
• To elucidate the origin and cellular uptake mechanisms of lysosomal glycosidases.

Summary:

• Analysis of glycoprotein glycan structures revealed that undegraded oligosaccharides and glycoasparagines in lysosomal storage diseases result from incomplete glycoprotein catabolism.
• A model for normal and pathological glycoprotein breakdown pathways was proposed.
• The study elucidated that lysosomal glycosidases are internalized via secretion-reuptake, intracellular trafficking, or cell surface uptake, involving specific membrane receptors recognizing phosphorylated oligomannosidic structures.

Impact:

• Provides fundamental insights into the molecular basis of lysosomal storage diseases.
• Clarifies the metabolic fate of glycoproteins and the biogenesis of lysosomal enzymes.
• Identifies specific molecular recognition mechanisms (phosphorylated oligomannosidic structures) crucial for lysosomal enzyme targeting.