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Pompe’s Disease : Amino Acid Changes and Effects
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Joel Bucci , Jennifer Ryan, and Dylan Storey
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)
Glycogen Storage and Utilization:
The human body metabolizes glucose using a process
called cellular respiration. This molecule is stored in a polymer
called glycogen. The pathway for conversion between these
two states is highly regulated by enzymatic processes and the
normal function of this cycle is required for life.
Introduction to the Genetics of the Disease:
Pompe disease is an autosomal recessive disease
affecting the function of alpha glycosidase in humans. To date
approximately 150 disease state alleles have been described.
Mutations vary in severity from zero activity to 12% of wild
type. While each allele affects the activity level of the enzyme
differently all are lethal. Carriers of the disease are able to live
normal lives and while they do not show diminished processing
capacity in vivo, in vitro assays do show a marked difference
when compared to wild type adults. While 150 mutations have
been characterized to date, five appear in the normal
population at a rate higher than that predicted by probabitlity
alone. This has led to a hypothesis of a founder affect in
several populations. (Table 1)
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.
Crystal structure of Alpha-glucosidase
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.
Reference:
Hirschhorn R et al,The Metabolic and Molecular Bases of Inherited Disease.
Hermans MM. et al. Biochem Journal.
5. Hirschhorn R et al.Increased frequency of Pompe disease in Afro-Americans..
Support kindly provided by:
Dept of BCMB; University of Tennessee, Knoxville
Table 1
Funding provided under NIH award:
LR25GM086761-01