P. Durand et al., Structural features of normal and mutant human lysosomal glycoside hydrolases deduced from bioinformatics analysis, HUM MOL GEN, 9(6), 2000, pp. 967-977
Lysosomal storage diseases are due to inherited deficiencies in various enz
ymes 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 wi
th the corresponding lysosomal diseases; however, no such three-dimensional
(3D) structure data are available for many lysosomal enzymes, Thus, we her
ein intend to illustrate for an audience of molecular geneticists how struc
ture 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 sequen
ce information available in data banks for the large group of glycoside hyd
rolases (clan GH-A) to which these human lysosomal enzymes belong, we could
deduce structure predictions for their catalytic domains and propose expla
nations for the molecular effects of mutations described in patients. In ad
dition, in the case of human P-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 Ins
ights into the effects of various mutations described in patients with Sly
disease. In a broader perspective, our work stresses that, in the context o
f a rapid increase in protein sequence information through genome sequencin
g, bioinformatics approaches might be highly useful for generating structur
e-function predictions based on sequence-structure interrelationships.