Gaucher disease type 1 is the most common lysosomal storage disorder, caused by glucocerebrosidase (GBA) deficiency. Imiglucerase (recombinant glucocerebrosidase) is used for enzyme replacement therapy (ERT). What modification of recombinant glucocerebrosidase is essential for its targeting to macrophage lysosomes?

• A High-mannose glycan residues are exposed on the enzyme surface to allow binding to mannose receptors on macrophages, directing endocytosis and lysosomal delivery ✓
• B The enzyme is conjugated with polyethylene glycol (PEG) to extend its plasma half-life and ensure passive uptake
• C The enzyme is linked to mannose-6-phosphate so that M6P receptors on macrophages direct it to lysosomes
• D The enzyme is administered with liposome carriers that fuse directly with lysosomal membranes

Explanation

Imiglucerase and velaglucerase alfa are produced with deliberately exposed high-mannose oligosaccharide residues (by selective trimming of outer sugar residues). Macrophages (the primary Gaucher cell) express C-type lectin mannose receptors (CD206) that avidly bind terminal mannose residues and internalise the enzyme by receptor-mediated endocytosis into lysosomes — where glucocerebrosidase then degrades accumulated glucocerebroside. This macrophage-targeted delivery avoids systemic toxicity. Note: mannose-6-phosphate (M6P) tagging is how most lysosomal enzymes are sorted intracellularly from the Golgi to lysosomes, but the ERT strategy here uses mannose receptor-mediated endocytosis, not the M6P pathway.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.