Expression cloning of cholesterol alpha-glucosyltransferase, a unique enzyme that can be inhibited by natural antibiotic gastric mucin O-glycans, from Helicobacter pylori.
Helicobacter pylori infects over half the world's population, but only 3% of those infected develop peptic ulcer, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. In H. pylori, alpha-glucosyl cholesterol constitutes more than 25% of cell wall lipids, and it has been suggested that alpha-glucosyl cholesterol is essential for H. pylori viability. Here, we identified cholesterol alpha-glucosyltransferase (CHLalphaGcT) using an expression cloning strategy and showed that this enzyme is distinctively inhibited by mucin-type O-glycans similar to those present in deeper portions of the gastric mucosa. Moreover, inactivation of CHLalphaGcT by homologous recombination led to H. pylori lethality. These results indicate that H. pylori CHLalphaGcT is a unique enzyme targeted by a natural antibiotic mucin and constitutes an excellent therapeutic target to prevent H. pylori-induced peptic ulcer, gastric carcinoma, and MALT lymphoma.
Lee
Heeseob
H
Glycobiology Program, Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Kobayashi
Motohiro
M
Wang
Ping
P
Nakayama
Jun
J
Seeberger
Peter H
PH
Fukuda
Minoru
M
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D003001:Cloning, Molecular / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006023:Glycoproteins; C047874:gastric mucus glycoproteins; D002784:Cholesterol; D005964:Glucosyltransferases