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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


  • Maier T
  • Strater N
  • Schuette CG
  • Klingenstein R
  • Sandhoff K
  • Saenger W


Journal of molecular biology

Publication Data

May 2, 2003

Associated Grants


Mesh Terms

  • 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