Lysosomal hydrolases, deficiencies

The GAGs are synthesized by the sequential actions of a battery of specific enzymes (glycosyltransferases, epimerases, suhotransferases, etc) and are degraded by the sequential action of lysosomal hydrolases. Genetic deficiencies of the latter result in mucopolysaccharidoses (eg, Hurler syndrome). 

Glycosphinqolipid Hydrolases. The deficiency of lysosomal glycosylhydrolases has been shown in a number of lipid storage diseases (as summarized in Table II) using cultured fibroblasts (29). ... 

Excessive accumulation of proteins, nucleic acids, carbohydrates, and lipids can result from deficiency of one or more lysosomal hydrolases. Lysosomal storage diseases are classified by the stored material. Accumulation of gly-cosaminoglycans results in mucopolysaccharidoses. Common causes of this disorder include Hunter syndrome, Hurler syndrome, and Sanfihppo syndrome. Sanfdippo syndrome is inherited in an autosomal recessive pattern and clinically evident by profound mental retardation, lack of normal developmental milestones, and significant language delay. Sanfdippo syndrome results in an excess of heparan sulfate and can be caused by a variety of enzyme deficiencies. 

Genetic Deficiencies of Glycoprotein Lysosomal Hydrolases Cause Diseases Such as a-Mannosidosis... 

Krabbe disease is caused by inherited deficiency of the lysosomal hydrolase galactocerebrosidase, the enzyme responsible for degradation of gaiactosyiceramide, a component of the myelin sheath, and other galactosphingosines (eg, psychosine). 

Genetic defects in the degradation of glycoproteins are representative of lysosomal storage disorders. Each disease is caused by a deficiency of a lysosomal hydrolase, accumulation and urinary excretion of substrates, a progressive clinical course and considerable phenotypic variation. These disorders also manifest the clinical symptoms normally associated with genetic mucopolysaccharidoses, namely coarse facies, dysostosis multiplex and/or ocular involvement. 

Lysosomal Glycosyl Hydrolase Deficiency and the Accumulation of Glycosphingolipids in Fibroblasts in "Glycolipidosis" ... 

Both avidin and the avidin-biotin complex are very stable to heat. To release biotin from avidin binding, autoclaving above 130°C is required, and free avidin is stable up to about 85°C. Avidin is also resistant to proteolysis and, as is obvious from the use of raw egg white diets to induce biotin deficiency, biotin cannot be released from avidin binding in the gastrointestinal tract. Lysosomal hydrolases do release biotin from avidin binding, and intravenously administered avidin-biotin can be a source of biotin. 

Breakdown of GSL occurs in the lysosomes, and inherited deficiencies of lysosomal hydrolases or of sphin-golipid activator proteins (SAPs, saposins) can give rise to sphingolipid storage diseases. The SAPs are necessary... 

Synthesis of glycosphingolipids and sulfoglycosphin-golipids involves the addition of sugar and sulfate residues to ceramide from UDP-sugar derivatives or the activated sulfate donor 3 -phosphoadenosine-5 -phosphosulfate (Chapter 17), and appropriate transferases. These pathways are discussed in Chapter 16. Catabolism of sphingolipids is by specific lysosomal hydrolases. Several inherited disorders associated with the deficiencies of these enzymes are discussed below. 

It is well known that the activities of various lysosomal hydrolases are strongly inhibited by heparan sulfate and other glycosaminoglycans (Avila and Convit, 1976). A possibility therefore exists that the primary defect in multiple sulfohydrolase deficiency is a mutation of hydrolase acting on heparan sulfate. An accumulation of this glycosaminoglycan may then inhibit other sulfohydrolases (Farooqui and Horrocks, 1984b). This possibility has not been tested. 

Defined as a deficiency of a lysosomal enzyme (acid hydrolase), which leads to the accumulation of a complex substrate within the lysosome... 

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