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Glycobiology Advance Access published online on June 3, 2006
Glycobiology, doi:10.1093/glycob/cwl010
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 5, 2006
Accepted May 31, 2006

Communication

Elucidation of the CMP-pseudaminic acid pathway in Helicobacter pylori: synthesis from UDP-N-acetyl-glucosamine by a single enzymatic reaction

Ian C Schoenhofen 1, David J McNally 1, Jean-Robert Brisson 1, and Susan M Logan 1 *

1 Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada

* To whom correspondence should be addressed.
Susan M Logan, E-mail: susan.logan{at}nrc-cnrc.gc.ca


  Abstract

Flagellin glycosylation is a necessary modification allowing flagellar assembly, bacterial motility, colonization, and hence virulence for the gastrointestinal pathogen Helicobacter pylori (Eaton et al., 1992; Josenhans et al., 2002; Schirm et al., 2003). A causative agent of gastric and duodenal ulcers (Dunn et al., 1997; Megraud, 2005), H. pylori heavily modifies its flagellin with the sialic acid-like sugar 5,7-diacetamido-3,5,7,9-tetradeoxy-L-glycero-{alpha}-L-manno-nonulosonic acid, or pseudaminic acid. Since this sugar is unique to bacteria, its biosynthetic pathway offers potential as a novel therapeutic target. We have identified six H. pylori enzymes, which reconstitute the complete biosynthesis of pseudaminic acid, and its nucleotide-activated form CMP-pseudaminic acid, from UDP-N-acetyl-glucosamine (UDP-GlcNAc). The pathway intermediates and final product were identified from monitoring sequential reactions with NMR spectroscopy, thereby confirming the function of each biosynthetic enzyme. Remarkably, conversion of UDP-GlcNAc to CMP-pseudaminic acid was achieved via a single enzymatic reaction. This represents the first complete in vitro enzymatic synthesis of a sialic acid-like sugar, and sets the groundwork for future small molecule inhibitor screening and design. Moreover, this study provides a strategy for efficient large-scale synthesis of novel medically-relevant bacterial sugars that has not been attainable by chemical methods alone.

Keywords: biosynthetic pathway elucidation/CMP-pseudaminic acid/enzymatic synthesis/flagellin glycosylation/sialic acid.
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