Lysosomes sialidases

Three different rare genetic metabolic defects in sialic acid metabolism are known, as indicated in Fig. 4.3.2 [3, 21] (1) free sialic acid storage disease (SASD Online Mendelian Inheritance in Man, OMIM 604369, 269920), a lysosomal membrane transporter defect (2) sialuria (OMIM 269921), a feedback inhibition defect in sialic acid biosynthesis (3) sialidosis (OMIM 256550), a breakdown defect of sialyloli-gosaccharides caused by a defect of lysosomal sialidase. In all these genetic defects, an increased amount of sialic acid can be found in tissues and or body fluids, either bound to OGSs as in (3), or in its free state as in (1) and (2). 

SASD must be discriminated from other disorders of sialic acid storage [3] (1) sialidosis and galactosialidosis, defects respectively in lysosomal sialidase and both sialidase and /1-galactosidase. (OMIM 256550 and 256540) (2) nonlysosomal sialuria (OMIM 269921). 

Fingerhut R, Van der Horst GT, Verheijen FW, Conzelmann E (1992) Degradation of ganglio-sides by the lysosomal sialidase requires an activator protein. Eur J Biochemi 208 623-629... 

K. E. Lukong, V. Seyrantepe, K. Landry, S. Tradel, A. Ahmad, W. A. Gahl, S. Lefrancois, C. R. Morales, and A. V. Pshezhetsky, Intracellular distribution of lysosomal sialidase is controlled by the internalization signal in its eytoplasmie tail, J. Biol Chem., 276 (2001) 46172-46181. 

S. Magesh, S. Moriya, T. Suzuki, T. Miyagi, H. Ishida, and M. Kiso, Design, synthesis, and biological evaluation of human sialidase inhibitors. Part 1 Selective inhibitors of lysosomal sialidase (NEUl), Bioorg. Med. Chem. Lett, 18 (2008) 532-537. 

F. Liang, V. Seyrantepe, K. Landry, R. Ahmad, A. Ahmad, N. M. Stamatos, and A. V. Pshezhetsky, Monocyte differentiation up-regulates the expression of the lysosomal sialidase, neul, and triggers its targeting to the plasma membrane via major histocompatibility complex class Il-positive compartments, J. Biol. Chem., 281 (2006) 27526-27538. 

Not only the deficiency of a hydrolytic enzyme, but also of other proteins required for sphingolipid degradation can cause a sphingolipid storage disease. Besides deficiencies of activator proteins, this is the case in galactosialidosis. This disease is characterized by the secondary deficiency of P-galactosidase and sialidase activity. The primary defect is due to mutations within the protective protein, which forms a stable complex with the GMl-p-galactosidase and the lysosomal sialidase [47]. 

Recent studies have shown that the lysosomal sialidase exists as a complex with P-galactosidase, protective protein, and other proteins including V-ace-... 

Lysosomal sialidases are always copurified with P-galactosidase when isolated from tissues such as bovine testis (Verheijen et aL, 1982), porcine testis (Yamamoto and Nishimura, 1987), and human placenta (Verheijen et aL, 1985, 1987 Hiraiwa et aL, 1987, 1988). This sialidase-P-galactosidase complex can... 

Most lysosomal sialidases preferentially catalyze the hydrolysis of the a2-3-linked sialic acids compared to the a2-6 residues. Exceptions to this are the enzymes from rabbit spermatozoal acrosomes (Srivastava and Abou-Issa, 1977) and human liver (Michalski et aL, 1982), which are more active on a2-6-linked sialic acids on glycoproteins, i.e., Cowper s gland mucin or submandibular gland mucin. The enzymes from human liver and porcine testis are more active on a2-8-linked sialic acids in colominic acid than other lysosomal enzymes (Table III). 

Michalski, J. C., Corfield, A. P., and Schauer, R., 1986, Properties of human liver lysosomal sialidase, Hoppe-SeylePs Z. Physiol. Chem. 367 715-722. 

Miyagi, T., and Tsuiki, S., 1984, Rat-liver lysosomal sialidase. Solubilization, substrate specificity and comparison with the cytosolic sialidase, Eur. J. Biochem. 141 75-81. 

Yamada, T., Tsuji, S., and Miyatake, T., 1983, Lysosomal sialidase deficiency in sialidosis with partial P-galactosidase deficiency, Biochim. Biophys. Acta 755 106-111. 

Sialidosis Two distinct clinical forms. The early onset form ( mucolipidosis I ) more severe with bony abnormalities, organomegaly, and neurological manifestations. Late-onset form with macular cherry red spots and intractable myoclonus with intact intellect Glycopeptides and oligosaccharides with terminal sialic acid Lysosomal sialidase (lysosomal a-neuramin idase)... 

The term sialidosis refers to a series of disorders, probably allelic, caused by genetic abnormalities in the lysosomal sialidase which removes the terminal sialic acids from carbohydrate chains of glycoproteins. The activity of the sialidase which cleaves the sialic acid moieties from some of the gangliosides, such as GM3 and polysialogangliosides, is not defective (see appropriate section in Scriver et al., 1995). Review of the earlier literature on sialidosis requires exceptional care. Some of the earlier cases reported as sialidosis may well have been cases of galactosialidosis, another distinct genetic disorder recognized much more recently (see below). 

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