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POMPE'S DISEASE. PRESENTATION BY FATOU NJIE. WHAT IS POMPE'S DISEASE?. Pompe's disease also referred to as Glycogen Storage Disease Type II or aicd maltase deficiency, is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid glucosidase. People

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    1. QUESTION? What are the three types of alpha-glucosidase and what is the function of this enzyme function?

    2. POMPES DISEASE PRESENTATION BY FATOU NJIE

    3. WHAT IS POMPES DISEASE? Pompes disease also referred to as Glycogen Storage Disease Type II or aicd maltase deficiency, is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid glucosidase. People affected with this disease are unable to degrade glycogen stored in the lysosome and thus leading to the accumulation of glycogen in lysosomal storage vacuoles.

    4. HISTORY OF THE DISEASE Existence of the disease was first described in 1932 by Dr JC Pompe. The disease is a rare neuromuscular genetic disorder that occurs in babies, children and adults who inherit a defective gene from each of their parents.

    5. HISTORY (CONT.) Pompes disease is the most devastating glycogen storage disease. The disease has been divided into three forms defined by age of onset and progression of symptoms. The three forms include infantile onset, juvenile onset and adult onset. In the infantile form of the disease, patients display cardiac impairment, which is fatal before two years of life.

    6. HISTORY(CONT.) Patients with juvenile or adult forms can present diaphragm involvement leading to respiratory failure. The adult onset symptoms involve generalized muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm.

    7. WHAT MAKES UP GLYCOGEN Glycogen is mostly found in the liver and skeletal muscles. It is a polymer of 120,000 glucose residues and is a primary carbohydrate storage form in animals.

    8. WHAT MAKES UP GLYCOGEN(CONT) The polymer is composed of units of glucose linked a-1-4 with branches occurring at a-1-6, approximately every 8-12 residues. The end of the molecule containing a free carbon number one on glucose is called a reducing end. The other ends are all called non-reducing ends

    9. SIZE OF GLYCOGEN Glycogen molecules are very large in size Therefore inability to degrade them results to a large accumulation of normal structure in the lysosomes of all cells. The excess storage of glycogen in the vacuoles is the consequence of defects in the lysosomal hydrolase.

    10. STRUCTURE OF GLYOGEN

    11. ALPHA-GLUCOSIDASE The acid a-glucosidase normally designated as GAA gene resides on chromosome 17q25, spanning 20 kb and composed of 20 exons. Glycogen storage disease type II has been shown to be caused by missense, nonsense and splice-site mutations, partial deletions and insertions. Some mutations are specific to certain ethnic groups.

    12. FORMS OF a-GLUCOSIDASE There are three common allelic forms of acid a-glucosidase that segregate in the general population. These forms are designated GAA1, GAA2 and GAA4. The normal function of acid a-glucosidase is to hydrolyze both a-1,4- and a-1,6-glucosidic linkages at acid Ph.

    13. ACTIVITY OF a-GLUCOSIDASE The activity of the enzyme leads to the complete hydrolysis of glycogen which is its natural substrate. As would be expected from this activity, deficiency in acid a-glucosidase leads to the accumulation of structurally normal glycogen in numerous tissues, most notably in cardiac and skeletal muscle.

    14. METABOLISM OF GLYCOGEN

    15. Activity of a-1,4-glucosidase in Lysosomal a-glucosidase The lysosomal a-1,4-glucosidase was found to be active at pH 4. However, its activity is not present in the liver, heart and skeletal muscles of children with pompes disease. Although the lysosomal a-1,4-glucosidase is often referred to as maltase, the enzyme is known to have a broader specificity in that it acts also on the outer chains of glycogen.

    16. ACTIVITY (CONT.) Studies have shown that a-1,4-glucosidase is able to catalyze the total degradation of glycogen to glucose. Also, its activity towards glycogen can be greatly stimulated by monovalent and divalent cations, and that the degree of stimulation is dependent upon pH.

    17. ACTIVITY (CONT.) The effect is so pronounced at pH 4 that the possibility might be considered that intralysosomal glycogen catabolism in vivo could be regulated within the organelle. Glucosidase has been purified from rat liver enzyme and was found to posses the ability to catalyze various transglucosylation reactions.

    18. ACTIVITY (CONT.) However, there is no evidence as to whether these transglucosylaton reactions should be regarded as having any physiological importance within the lysosome. It clearly shows that a-1,4-glucosidase is present in lysosome from rat liver but its ability to debranch glycogen granules is unknown.

    19. Kinetics of a-glucosidase Studies done on the kinetics of a-glucosidase shows differences in its response to cation concentration and pH. This suggested that the enzyme have more than one catalytically active binding site as well as at least one separate inhibitory site. One of the two catalytic sites could bind maltose, as well as other maltosidically linked oligosaccharides of low molecular weight.

    20. STRUCTURE OF MALTOSE(a glucosyl-glucose disaccharide)

    21. Kinetics of a-glucosidase(cont.) The same binding site also have affinity for the a-1,6-glucosidasidically linked isomaltase since it is a competitive inhibitor of maltose hydrolysis. The other catalytic binding sites might bind polysaccharide substrate such as glycogen and would be the locus of a-1,4-glucosidase action on such molecules.

    22. Catalytic Site of Lysosomal a-Glucosidase The primary structure of lysosomal a-glucosidase was studied through molecular cloning and analysis of cDNA and genomic sequences. It was found that the cDNA codes for a protein of 952 amino acids with an apparent molecular mass of 110 kDa.

    23. Catalytic Site of Lysosomal a-Glucosidase(cont) The residues that were found in the catalytic site of this enzyme were located in a peptide extending from Asp-513 to Asn-520 in mammalian cells. These amino acid substitutions were made by site-directed mutagenesis.

    24. Oligonucleotides used for mutagenesis

    25. MUTATION AT THE CATALYTIC SITE Substitutions were made at positions Asp-513, Trp-516, and Asp-518 to obtain direct information on the role of potentially important residues in the catalytic site region.

    26. MUTATION AT THE CATALYTIC SITE(CONT.) The substitution of Asp-513 by Glu-513 had the most dramatic effect as it causes the blockage of both the posttranslational modification and the intracellular transport of a-glucosidase.

    27. MUTATION AT THE CATALYTIC SITE(CONT.) The substitution of Trp-516 by Arg-516 leads to loss of catalytic function. Tryptophan has a non-polar side chain and practically no acidic or basic properties. Thus the inactivation is more likely due to an altered charge distribution.

    28. Regulation of GAA The regulation of GAA may be quite complex according to analysis of results obtained from resent experiments. Therefore this lysosomal enzyme may have still unrecognized physiological roles in development. The discovery of the GAA gene however, has led to rapid progress in understanding the biological mechanisms and properties of the enzyme.

    29. Treatment An enzyme replacement called myozyme has been shown to be a safe and effective treatment for Pompe disease. Researchers are still working on having a better understanding of the mechanism behind the uptake and degradation of glycogen by GAA .

    30. QUESTIONS?

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