Role of lipid A palmitoylation in bacterial pathogenesis.
The presence of palmitate in a minor fraction of lipid A has been known since the chemical structure of lipid A was first elucidated, but the functional importance in bacterial pathogenesis of regulated lipid A palmitoylation has become clear only recently. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP. The isolation of pagP mutants from pathogenic Gram-negative bacteria has revealed that palmitoylated lipid A can both protect the bacterium from certain host immune defenses and attenuate the ability of lipid A to activate those same defenses through the TLR4 signal transduction pathway. The mechanisms by which bacteria regulate the incorporation of palmitate into lipid A strikingly reflect the corresponding organism's pathogenic lifestyle. Variations on these themes can be illustrated with the known pagP homologs from Gram-negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is now lending itself both as a target for the development of anti-infective agents, and as a tool for the synthesis of lipid A-based vaccine adjuvants and endotoxin antagonists.
Bishop
Russell E
RE
Departments of Laboratory Medicine and Pathobiology, and Biochemistry, University of Toronto, Ontario, Canada. russell.bishop@utoronto.ca
Kim
Sang-Hyun
SH
El Zoeiby
Ahmed
A
D000217:Acyltransferases / Q000502:physiology*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000472:pathogenicity; D001425:Bacterial Outer Membrane Proteins; D002462:Cell Membrane; D029968:Escherichia coli Proteins / Q000502:physiology*; D008050:Lipid A / Q000378:metabolism*; D008969:Molecular Sequence Data; D010168:Palmitates / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D008050:Lipid A; D010168:Palmitates; D000217:Acyltransferases; C468520:PagP protein, E coli