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Glycobiology Advance Access originally published online on May 5, 2008
Glycobiology 2008 18(7):549-558; doi:10.1093/glycob/cwn037
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

{alpha}1,4GlcNAc-capped mucin-type O-glycan inhibits cholesterol {alpha}-glucosyltransferase from Helicobacter pylori and suppresses H. pylori growth

Heeseob Lee2,5, Ping Wang4,5, Hitomi Hoshino4,6, Yuki Ito4,5, Motohiro Kobayashi6, Jun Nakayama6, Peter H Seeberger3,5 and Minoru Fukuda1,5

5 Tumor Microenvironment Program, Glycobiology Unit, Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
6 Department of Pathology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan

1 To whom correspondence should be addressed: Tel: +81-858-646-3144; Fax: +81-858-646-3193; e-mail: minoru{at}burnham.org

Received on January 29, 2008; revised on April 23, 2008; accepted on April 29, 2008

Helicobacter pylori infects over half of the world's population and is thought to be a leading cause of gastric ulcer, gastric carcinoma, and gastric malignant lymphoma of mucosa-associated lymphoid tissue type. Previously, we reported that a gland mucin (MUC6) present in the lower portion of the gastric mucosa containing {alpha}1,4-N-acetylglucosamine ({alpha}1,4GlcNAc)-capped core 2-branched O-glycans suppresses H. pylori growth by inhibiting the synthesis of {alpha}-glucosyl cholesterol, a major constituent of the H. pylori cell wall (Kawakubo et al. 2004. Science. 305:1003-1006). Therefore, we cloned the genomic DNA encoding cholesterol {alpha}-glucosyltransferase (HP0421) and expressed its soluble form in Escherichia coli. Using this soluble HP0421, we show herein that HP0421 sequentially acts on uridine diphosphoglucose and cholesterol in an ordered Bi-Bi manner. We found that competitive inhibition of HP0421 by {alpha}1,4GlcNAc-capped core 2-branched O-glycan is much more efficient than noncompetitive inhibition by newly synthesized {alpha}-glucosyl cholesterol. Utilizing synthetic oligosaccharides, {alpha}-glucosyl cholesterol, and monosaccharides, we found that {alpha}1,4GlcNAc-capped core 2-branched O-glycan most efficiently inhibits H. pylori growth. These findings together indicate that {alpha}1,4GlcNAc-capped O-glycans suppress H. pylori growth by inhibiting HP0421, and that {alpha}1,4GlcNAc-capped core 2 O-glycans may be useful to treat patients infected with H. pylori.

Key words: {alpha}4GlcNAc-capped core 2-branched O-glycan / cholesterol {alpha}-glucosyltransferase / growth inhibition / Helicobacter pylori / novel antibiotics

2 Present address: Department of Food Science and Nutrition, Pusan National University, Busan 609-735, Korea.

3 Alternate address: Laboratory for Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zurich, Wolfgang-Pauli Str. 10, 8093 Zurich, Switzerland.

4 These authors equally contributed to this work.


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