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Papers In Press, published online ahead of print January 18, 2006
J. Biol. Chem, 10.1074/jbc.M512987200
Submitted on December 5, 2005
Revised on January 12, 2006
Accepted on January 18, 2006

Structural and functional characterization of PseC, an aminotransferase involved in the biosynthesis of Pseudaminic acid, an essential flagellar modification in helicobacter pylori

Ian C. Schoenhofen, Vladimir V Lunin, Jean-Phillipe Julien, Yunge Li, Eunice Ajamian, Allan Matte, Miroslav Cygler, Jean-Robert Brisson, Annie Aubry, Susan M. Logan, Smita Bhatia, Warren W. Wakarchuk, and N. Martin Young

Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6

Corresponding Author: Martin.Young{at}nrc-cnrc.gc.ca

Helicobacter pylori flagellin is heavily glycosylated with the novel sialic acid–like nonulosonate, pseudaminic acid (Pse). The glycosylation process is essential for assembly of functional flagellar filaments and consequent bacterial motility. As motility is a key virulence factor for this and other important pathogens, the Pse biosynthetic pathway offers potential for novel therapeutic targets. From recent NMR analyses, we determined that the conversion of UDP-a-D-GlcNAc to the central intermediate in the pathway, UDP-4-amino-4,6-dideoxy-ß-L-AltNAc, proceeds by formation of UDP-2-acetamido-2,6-dideoxy-ß-L-arabino-4-hexulose by the dehydratase/epimerase PseB (HP0840) followed with amino transfer by the aminotransferase, PseC (HP0366). The central role of PseC in the H. pylori Pse biosynthetic pathway prompted us to determine crystal structures of the native protein, its complexes with pyridoxal phosphate alone and in combination with the UDP-4-amino-4,6-dideoxy-ß-L-AltNAc product, the latter being converted to the external aldimine form in the enzyme’s active site. In the binding site, the AltNAc sugar ring adopts a 4C1 chair conformation which is different from the predominant 1C4 form found in solution. The enzyme forms a homodimer where each monomer contributes to the active site, and these structures have permitted the identification of key residues involved in stabilization, and possibly catalysis, of the ß-L-arabino intermediate during the amino transfer reaction. The essential role of Lys183 in the catalytic event was confirmed by site-directed mutagenesis. This work presents for the first time a nucleotide-sugar aminotransferase co-crystallized with its natural ligand, and in conjunction with the recent functional characterization of this enzyme, will assist in elucidating the aminotransferase reaction mechanism within the Pse biosynthetic pathway.


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