P Durand, Fabrega, S, Henrissat, B, Mornon, JP and Lehn, P (2000), "Structural features of normal and mutant human lysosomal glycoside hydrolases deduced from bioinformatics analysis.", Hum Mol Genet, 9, 6: 967-77.
Abstract: Lysosomal storage diseases are due to inherited deficiencies
in various enzymes involved in basic metabolic processes. As with
other genetic diseases, accurate structure data for these enzymatic
proteins should help in better understanding the molecular effects of
mutations identified in patients with the corresponding lysosomal
diseases; however, no such three-dimensional (3D) structure data
are available for many lysosomal enzymes. Thus, we herein intend to
illustrate for an audience of molecular geneticists how structure
information can nonetheless be obtained via a bioinformatics approach
in the case of five human lysosomal glycoside hydrolases. Indeed,
using the two-dimensional hydrophobic cluster analysis method to
decipher the sequence information available in data banks for the
large group of glycoside hydrolases (clan GH-A) to which these human
lysosomal enzymes belong, we could deduce structure predictions for their
catalytic domains and propose explanations for the molecular effects of
mutations described in patients. In addition, in the case of human
beta-glucuronidase for which experimental 3D data have been reported, we also
show here that bioinformatics methods relying on the available 3D
structure information can be used to obtain further insights into the
effects of various mutations described in patients with Sly disease.
In a broader perspective, our work stresses that, in the context
of a rapid increase in protein sequence information through genome
sequencing, bioinformatics approaches might be highly useful for generating
structure-function predictions based on sequence-structure interrelationships.
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