Mannose-6-phosphate pathway: a review of its role in lysosomal function and dysfunction (2023)

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The mannose-6-phosphate pathway: from amoeba to human

The mannose-6-phosphate dependent mechanism for routing of lysosomal enzymes was first described in mammalian cells involving the sequential action of the proteins mentioned above: GlcNAc-1-phosphotransferase, N-acetylglucosamine-1-phosphodiester α-N-acetyl -glucosaminidase and the two mannose-6-phosphate receptors. An identical mechanism was then demonstrated in birds (chicken) and amphibians (Xenopus) cells [4], suggesting that the mannose-6-phosphate pathway was probably shared by all


GlcNac phosphotransferase is a 540 kDa hexameric transmembrane enzyme residing in the Golgi composed of three subunits, α2B2C2, which catalyzes the first step in the formation of the M6P recognition marker in lysosomal enzymes (Fig.1). This enzyme is encoded by two different genes:GNPTABEGNPTG, encoding the α/β subunits and the α subunit, respectively. OGNPTABThe gene contains 21 exons and spans 85 kb on chromosome 12q23.3. Encodes a 1256 amino acid protein with a predicted molecule

Defective GlcNAc-1 phosphotransferase causes mucolipidosis II and III

Defective GlcNAc-1-phosphotransferase causes two distinct human lysosomal storage diseases, mucolipidosis II (ML II) and mucolipidosis III (ML III), which are among the few lysosomal storage diseases associated with defects in non-lysosomal proteins. ML II, also known as I-cell disease, is characterized by a complete loss of GlcNAc-1 phosphotransferase activity, regardless of whether ML III, often referred to as pseudo-Hurler polydystrophy, manifests when enzyme activity is reduced [ 58], [59]. Both in ML II and in

Conclusion and future prospects

Much has been learned in recent decades about the mannose-6-phosphate dependent pathway, the main cellular pathway for transporting soluble hydrolases to the lysosome. Its main functional components are now reasonably well characterized, both at a biochemical and genetic level. However, some important questions remain unanswered. Although the key enzymes necessary for the formation of the mannose-6-phosphate recognition signal have been identified, the protease cleaves and cleaves through it.


This work was supported byFKT- ProjectPIC/IC/83252/2007( Coutinho MF is an FCT scholarship holder (SFRH/BD/48103/2008).

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