This project was prepared as part of a BioQUEST faculty development workshop entitled PEER Workshop: Using Bioinformatics in Biological Problem Solving at SCALE-IT, NIMBIOS in August 2009. The BioQUEST Curriculum Consortium is committed to the reform of undergraduate biology instruction through an emphasis on engaging students in realistic scientific practices. This approach is sometimes characterized as an inquiry driven approach and is captured in BioQUEST's three P's (problem-posing, problem-solving, and peer-persuasion). As part of this workshop groups of faculty were encouraged to initiate innovative curricular projects. We are sharing these works in progress in the hope that they will stimulate further exploration, collaboration and development. Please see the following links for additional information:

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Looking at amino acid residue changes in alpha glucosidase.
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Possible Audiences:

People who have Pompe disease or are carriers of the disease.  


Brief Overview:

Pompe disease is an autosomal recessive disease affecting the function of alpha glucosidase in humans. To date approximately 150 disease state alleles have been described (Link) . Mutations vary in severity from zero activity to 12% of wildtype. While each allele affects the activity level of the enzyme differently all are lethal. One article that we found centered on one adult American that suffered from Glycogen Storage Disease Type II. Hermans et. al. found that in this instance, the disease was caused by a deficiency in lysosomal alpha-glucosidase. The small amount of alpha-glucosidase that was present displayed a lower molecular mass, phosphorylation capabilities and proteolytic processing abilities. There were three mutations, one of which resulted in no change in alpha-glucosidase function or molecular mass. The substitution of Thr927->Ile resulted in a deletion of one glycosylation site, thus decreasing the molecular weight of the alpha-glucosidase proteins. The change from Asp645->Glu drastically lowered the protein's functions as a transporter, in phosphorylation, and in proteolytic processing. This change is responsible for the severity of GSD Type II in this individual. (Hermans 1993) The substitution of Isoleucine instead of Threonine causes the loss of a glycosylation site and subsequent loss of molecular mass. We believe this results from the size difference between Isoleucine and Threonine as well as the huge difference in water affiliation. While Threonine is hydrophilic, Isoleucine is extremely hydrophobic. We were unable to find out where this site is located on the folded protein. If it is located on the outside of the structure, then this change can cause a major loss of function and disruption of tertiary folding because the Isoleucine prefers to be away from the solvent. Another thought is that it could somehow force the protein to fold in such a way as to prevent access to vital binding sites. One major amino acid substitution which leads to genetic disorders is Asp645, which is changed into a glutamate. Both amino acids have similiar properties but differ in size. Both are hydrophilic and negatively charged, but glutamate is larger. This difference in size could contribute to genetic disorders. Specifically, this substitution contributes to problems in transport, phosphorylation, and proteolytic processing for alpha glucosidase to create useable sugars.  


Resources and References:

Hermans MM. et. al. Biochem Journal. 1993. Picture of pathway: 8/7/09.