title: The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease.
abstract: 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.
authors.affiliation: Institut für Chemie Kristallographie, Freie Universität Berlin, Takustrasse 6, 14195 Berlin, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Maier
authors.forename: Norbert
authors.initials: N
authors.lastname: Strater
authors.forename: Christina G
authors.initials: CG
authors.lastname: Schuette
authors.forename: Ralf
authors.initials: R
authors.lastname: Klingenstein
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Wolfram
authors.initials: W
authors.lastname: Saenger
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000208:Acute Disease; D000483:Alleles; D001419:Bacteria / Q000201:enzymology; D001665:Binding Sites; D002384:Catalysis; D002908:Chronic Disease; D018360:Crystallography, X-Ray; D019281:Dimerization; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D006358:Hot Temperature; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D012326:RNA Splicing; D012497:Sandhoff Disease / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D001619:beta-N-Acetylhexosaminidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C023735:2-acetamido-2-deoxy-D-glucono-(1,5)-lactone; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine