title: Flexibility and mutagenic resiliency of glycosyltransferases.
abstract: The human blood group A and B antigens are synthesized by two highly homologous enzymes, glycosyltransferase A (GTA) and glycosyltransferase B (GTB), respectively. These enzymes catalyze the transfer of either GalNAc or Gal from their corresponding UDP-donors to αFuc1-2βGal-R terminating acceptors. GTA and GTB differ at only four of 354 amino acids (R176G, G235S, L266M, G268A), which alter the donor specificity from UDP-GalNAc to UDP-Gal. Blood type O individuals synthesize truncated or non-functional enzymes. The cloning, crystallization and X-ray structure elucidations for GTA and GTB have revealed key residues responsible for donor discrimination and acceptor binding. Structural studies suggest that numerous conformational changes occur during the catalytic cycle. Over 300 ABO alleles are tabulated in the blood group antigen mutation database (BGMUT) that provides a framework for structure-function studies. Natural mutations are found in all regions of GTA and GTB from the active site, flexible loops, stem region and surfaces remote from the active site. Our characterizations of natural mutants near a flexible loop (V175M), on a remote surface site (P156L), in the metal binding motif (M212V) and near the acceptor binding site (L232P) demonstrate the resiliency of GTA and GTB to mutagenesis.
authors.affiliation: Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-1799, Copenhagen V, Denmark.
authors.forename: Marie Lund
authors.initials: ML
authors.lastname: Bay
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cuesta-Seijo
authors.forename: Joel T
authors.initials: JT
authors.lastname: Weadge
authors.forename: Mattias
authors.initials: M
authors.lastname: Persson
authors.forename: Monica M
authors.initials: MM
authors.lastname: Palcic
mesh_terms: D001483:Base Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D017931:DNA Primers; D016695:Glycosyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation
chemical_list: D017931:DNA Primers; D016695:Glycosyltransferases