ACTIVE-SITE MOTIFS OF LYSOSOMAL ACID-HYDROLASES - INVARIANT FEATURES OF CLAN GH-A GLYCOSYL HYDROLASES DEDUCED FROM HYDROPHOBIC CLUSTER-ANALYSIS

The dan GH-A is a group of more than 200 proteins representing nine es tablished families of glycosyl hydrolases that act on a large variety of substrates. This dan includes five enzymes implicated in lysosomal storage diseases: beta-glucuronidase (Sly disease), beta-glucocerebros idase (Gaucher disease), beta-galactosidase (Landing disease and Morqu io type B disease), beta-mannosidase (mannosidosis) and alpha-L-iduron idase (Hurler-Scheie disease). Examination of known 3D structures from some families of the dan allowed us to deduce structural and function al features shared by these proteins. We then used the hydrophobic clu ster analysis method to study the protein sequences of the entire dan. Our results reveal that, despite low levels of sequence identity, all the proteins of the dan (including the aforementioned lysosomal enzym es) likely share a similar catalytic domain consisting of an (alpha/be ta)(8) barrel with conserved functional amino acids located at the C-t erminal ends of six of the eight strands constituting the beta-barrel. Interestingly, several mutations reported to be responsible for lysos omal storage diseases are located within these conserved regions of th e lysosomal enzyme catalytic domains.