The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease.
Human lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3A resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S.
Pubmed ID: 12706724 RIS Download
Acetylglucosamine | Acute Disease | Alleles | Bacteria | Binding Sites | Catalysis | Chronic Disease | Crystallography, X-Ray | Dimerization | Hexosaminidase A | Hexosaminidase B | Hot Temperature | Humans | Models, Molecular | Mutation | Point Mutation | Protein Structure, Quaternary | RNA Splicing | Sandhoff Disease | Sequence Homology, Amino Acid | Substrate Specificity | beta-N-Acetylhexosaminidases