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Pompes Disease Amino Acid Changes and Effects
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-gtIle resulted in a
deletion of one glycosylation site, thus
decreasing the molecular weight of the
alpha-glucosidase proteins. The change from
Asp645-gtGlu drastically lowered the proteins
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.
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)
Crystal structure of Alpha-glucosidase
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
Funding provided under NIH award LR25GM086761-01