title: Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship.
abstract: Strategies utilizing Toll-like receptor 4 (TLR4) agonists for treatment of cancer, infectious diseases, and other targets report promising results. Potent TLR4 antagonists are also gaining attention as therapeutic leads. Though some principles for TLR4 modulation by lipid A have been described, a thorough understanding of the structure-activity relationship (SAR) is lacking. Only through a complete definition of lipid A-TLR4 SAR is it possible to predict TLR4 signaling effects of discrete lipid A structures, rendering them more pharmacologically relevant. A limited 'toolbox' of lipid A-modifying enzymes has been defined and is largely composed of enzymes from mesophile human and zoonotic pathogens. Expansion of this 'toolbox' will result from extending the search into lipid A biosynthesis and modification by bacteria living at the extremes. Here, we review the fundamentals of lipid A structure, advances in lipid A uses in TLR4 modulation, and the search for novel lipid A-modifying systems in extremophile bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Scott
authors.affiliation: Institute of Marine & Environmental Technology, University of Maryland Center for Environmental Science, Baltimore, MD 21202, United States.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Oyler
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.affiliation: Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD 21201, United States. Electronic address: rkernst@umaryland.edu.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004798:Enzymes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008050:Lipid A / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D050155:Lipogenesis; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004798:Enzymes; D008050:Lipid A; D051197:Toll-Like Receptor 4
keywords: Lipid A modifying enzymes; Lipid A structure; Marine bacteria; TLR4 agonists; TLR4 antagonists; TLR4 immunomodulation