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# 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.

## In detail

- 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.

**Also called**
Mannose 6-phosphate pathway

## Clinical notes

- 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.

## Related conditions

- [I-cell disease (mucolipidosis II)](https://durgical.com/en/conditions/i-cell-disease/)
- [Hurler syndrome (mucopolysaccharidosis type I)](https://durgical.com/en/conditions/hurler-syndrome/)

## Related

- [Cell organelles and their metabolism](https://durgical.com/en/biochemistry/topics/cell-organelles-and-their-metabolism/)
- [Lysosomal storage diseases](https://durgical.com/en/biochemistry/topics/lysosomal-storage-diseases/)
- [Glycosaminoglycans (mucopolysaccharides)](https://durgical.com/en/biochemistry/topics/glycosaminoglycans/)
- [Membrane transport](https://durgical.com/en/biochemistry/topics/membrane-transport/)

## Test yourself

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.

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

Sources: [Lysosome Vesicle Biogenesis](https://reactome.org/PathwayBrowser/#/R-HSA-432720) (Reactome, 2026); [Transport to the Golgi and subsequent modification](https://reactome.org/PathwayBrowser/#/R-HSA-948021) (Reactome, 2026); [Asparagine N-linked glycosylation](https://reactome.org/PathwayBrowser/#/R-HSA-446203) (Reactome, 2026); [Mannose 6-phosphate (CID 6101690)](https://pubchem.ncbi.nlm.nih.gov/compound/6101690) (PubChem, NCBI, 2026) · Public domain; [GNPTAB gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/gnptab/) (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.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/topics/mannose-6-phosphate-tagging/