Enzymes lysosomal, targeting

An important additional pathway is indicated in reactions I and II of Figure 47-9. This involves enzymes destined for lysosomes. Such enzymes are targeted to the lysosomes by a specific chemical marker. In reaction I, a residue of GIcNAc-1-P is added to carbon 6 of one or more specific Man residues of these enzymes. The reaction is catalyzed by a GIcNAc phosphotransferase, which uses UDP-GlcNAc as the donor and generates UMP as the other product ... 

The I-cell patient has proved invaluable for elucidation of the complex nature of intracellular packaging and sorting of lysosomal enzymes. The physiological importance of this signal-mediated pathway is evident in that fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy secrete rather than target most of their lysosomal enzymes. Thus, the molecular theme of I-cell disease is that of faulty lysosomal targeting, the inability to transport (i.e., sort) lysosomal enzymes from their site of synthesis to the lysosome. 

In 2007 we characterized a novel transmembrane type-I isoform of the prostatic acid phosphatase enzyme (TMPAP) as the product of a splice variant of the same gene encoding the secreted form (sPAP). This transmembrane type-I isoform contains a tyrosine-based lysosomal targeting (YxxO) motif at the... 

FIGURE 27-36 Phosphorylation of mannose residues on lysosome-targeted enzymes. /V-Acetylglucosamine phosphotransferase recognizes some as yet unidentified structural feature of hydrolases destined for lysosomes. 

Within the Golgi, enzymes are targeted for endosomes (and eventually lysosomes) by addition of mannose 6-phosphate residues that bind to mannose 6-phosphate receptor proteins in the Golgi membrane. The mannose 6-phosphate receptors together with their bound acid hydrolases are incorporated into the clathrin-coated Golgi transport vesicles and released. The transport vesicles lose their clathrin coat and then fuse with the late endosomal membrane. The acidity of the endosome releases the acid hydrolases from the receptors into the vesicle lumen. The receptors are eventually recycled back to the Golgi. 

Coates et al. 1982), lymphocytes (Coates et al. 1975) and liver cells (Ameis et al. 1994). After synthesis in the endoplasmic reticulum, the enzyme is targeted to the lysosomal compartment (Sando and Henke 1982). Ameis et al. (1994) give a complete nucleotide sequence and deduced protein sequence for human LAL cDNA. There are some nucleotide differences of liver and fibroblast LAL cDNA. 

One limitation of enzyme replacement therapy is the targeting of enzyme proteins to appropriate sites of substrate accumulation. Administration of a cholesterol esterase conjugated to albumin results in the degradation of pathologic cholesterol ester accumulations within the lysosomes of fibroblasts from a patient with cholesterol ester storage disease (246). 

I-Cell Disease Results From Faulty Targeting of Lysosomal Enzymes... 

As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes the lysosomes thus accumulate many different... 

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