Mannose 6-phosphate tagging (sending enzymes to the lysosome) !

In the Golgi, lysosomal enzymes get a mannose 6-phosphate tag; without it they leave the cell instead of reaching the lysosome.

Updated 2026-11-01

Key facts

Step 1 (cis-Golgi): GlcNAc-1-phosphotransferase (genes GNPTAB and GNPTG) adds N-acetylglucosamine 1-phosphate onto mannoses of the hydrolase.
Step 2: the "uncovering enzyme" (NAGPA) removes the N-acetylglucosamine and exposes mannose 6-phosphate.
In the trans-Golgi, mannose 6-phosphate receptors capture the enzyme and carry it in clathrin-coated vesicles to the late endosome.
The acidic endosome releases the enzyme; the receptor returns to the Golgi.
If the phosphotransferase fails (I-cell disease), hydrolases are secreted: high in plasma, absent in lysosomes.

1. Lysosomal hydrolases are made in the rough ER and receive high-mannose N-glycans.
2. The phosphotransferase recognises a surface patch of the protein (not a linear sequence), so it tags only lysosomal hydrolases.
3. In the trans-Golgi network, the cation-independent and cation-dependent mannose 6-phosphate receptors separate these enzymes from secretory ones.
4. Some receptor sits on the plasma membrane and recovers secreted enzymes by endocytosis; this is how replacement enzymes get in.
5. Some tissues (hepatocytes, leukocytes) use other delivery routes and partly keep lysosomal activity in I-cell disease.

I-cell disease (mucolipidosis II): fibroblasts with inclusions, very high plasma hydrolases, coarse features and dysostosis from birth.
Mucolipidosis III (pseudo-Hurler) keeps some phosphotransferase activity and is milder.
Replacement enzymes are made rich in mannose 6-phosphate (or mannose for macrophages, as in Gaucher) so that cells take them up.

Think of the answer, then tap the question to see it.

Which enzyme fails in I-cell disease?

Golgi GlcNAc-1-phosphotransferase, which starts the mannose 6-phosphate tag.

Why are lysosomal hydrolases high in plasma in I-cell disease?

Without mannose 6-phosphate, Golgi receptors do not capture them, so they leave by the secretory route.

What releases a hydrolase from its mannose 6-phosphate receptor?

The acidic pH of the late endosome; the empty receptor goes back to the Golgi.

Educational information, not medical advice. For any symptom, see a health professional.

Sources: Lysosome Vesicle Biogenesis (Reactome, 2026); Transport to the Golgi and subsequent modification (Reactome, 2026); Asparagine N-linked glycosylation (Reactome, 2026); Mannose 6-phosphate (CID 6101690) (PubChem, NCBI, 2026) · Public domain; GNPTAB gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.