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Glycobiology Advance Access published online on May 5, 2008
Glycobiology, 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 Lee2,4, Hitomi Hoshino3,6, Ping Wang2,6, Yuki Ito2,6, Motohiro Kobayashi3, Jun Nakayama3, Peter H. Seeberger2,5 and Minoru Fukuda1,2

2 Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037
3 Department of Pathology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
5 Alternate address: Laboratory for Organic Chemistry, Swiss Federal Institute of Technology (ETH) Zurich, Wolfgang-Pauli Str. 10, 8093 Zurich, Switzerland

1 To whom correspondence should be addressed: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037; Tel. 858-646-3144; Fax 858-646-3193; E-mail: minoru{at}burnham.org

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

Helicobacter pylori infects over half 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}1,4GlcNAc-capped core 2-branched O-glycans suppresses H. pylori growth by inhibiting 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 UDP-Glc 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 non-competitive 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 / novel antibiotics / cholesterol {alpha}-glucosyltransferase / growth inhibition / Helicobacter pylori

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

6 These authors equally contributed to this work


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