Lysosomes sialic acid

Verheijen FW, Mancini GM (2003) Lysosomal sialic acid transporter sialin (SLC17A5) sialic acid storage disease (SASD). In Broer S, Wagner CA (eds) Membrane Transporter Diseases. Kluwer Academic/Plenum, New York, pp 233-239... 

Glucuronic acid and sialic acid are normally present in conjugated forms. After degradation of these components in lysosomes, the free monosaccharides are released by a specific membrane transport system. The lysosomal sialic acid transporter from rat liver has been purified to apparent homogeneity in a reconstitutively active form. The transporter recognized structurally different types of acidic monosaccharides such as sialic acid, glucuronic acid, and iduronic acid. The transport was proton gradient dependent, and saturable with a of approximately 0.4mM [211]. 

Sialin was first identified as the product of the gene defective in sialidosis, a lysosomal storage disorder. The transporter mediates the movement of sialic acid out of lysosomes by coupling to the proton electrochemical gradient across the lysosomal membrane. Unlike the vesicular neurotransmitter transporters which are antiporters, sialin is a sympoiter with sialic acid and protons both moving out of the lysosome. 

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). 

The lysosomal disorder SASD is characterized by accumulation of the free acid monosaccharide sialic acid in the lysosomal compartment of the cell. Diagnosis is based on the demonstration of abnormal excretion of free, not OGS-bound sialic acid in urine, coupled with accumulation of free sialic acid in cultured fibroblasts, and on microscopic evidence of vacuoles (increased and swollen lysosomes filled with light electron-lucent material in skin biopsy and peripheral blood lymphocytes). The inheritance is autosomal recessive. There are different clinical forms of this disorder an adult form, called Salla disease (SD) or Finnish sialuria (OMIM 604369) infantile SASD (ISSD OMIM 269920) and an intermediate form, severe Salla disease [3,16]. 

All clinical forms of the disease are due to a defect in the lysosomal membrane transporter for sialic acid necessary for the export of sialic acid out of the lysosome [11]. The gene coding for this transporter, SLC17A5, contains 11 exons and encodes a 495-amino-acid transmembrane protein, sialin [20]. 

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). 

Mancini GM, Beerens CE, Aula PP, Verheijen FW (1991) Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. J Clin Invest 87 1329-1335... 

N-acetylagalactosamine 1-phosphtransferase lysosomal hydrolases Mucolipin 1, Ca++/cation ion channel Sialic acid transporter... 

Three enzyme systems are required for the catabolism of sialic acids 0-acetylesterases, sialidases and lyases. Furthermore, a sialic acid transporter has been described (section 10.5), which carries liberated sialic acids from lysosomes into the cytosol, where they are either degraded by the lyase or recycled after activation with CTP (section 8.3). Sialic acid permeases provide bacteria with sialic acids for nutritional purposes (section 9.4). 

Lysosomal accumulation of free sialic acid occurs in two phenotypically distinct inherited metabolic disorders, Salla disease and infantile sialic acid storage disease [1096]. Salla disease is an autosomal recessive lysosomal storage disorder and was first observed in patients of Fiimish ancestry, but also occurs outside Finland. The clinical symptoms are a slow progressive psychomotor retardation, impaired speech, ataxia and a prolonged course. Sialic acid accumulates in the lysosomes due to a defective efflux into the cytosol. The genetic defect affects the function of the specific transport protein for sialic acid and other acidic monosaccharides in the lysosomal membrane [1097]. The Salla disease locus... 

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