title: Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity.
abstract: Lipopolysaccharides (LPS, endotoxin) represent a major virulence factor of Gram-negative bacteria, which can cause septic shock in mammals, including man. The lipid anchor of LPS to the bacterial outer membrane, lipid A, exhibits a peculiar chemical structure, harbours the 'endotoxic principle' of LPS and is also responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against endotoxically active LPS. By applying orientation measurements with attenuated total reflectance (ATR) infrared spectroscopy on hydrated lipid A samples, we show here that these different biological activities are directly correlated to the intrinsic conformation of lipid A. Bisphosphoryl-hexaacyl lipid A molecules with an asymmetric (4/2) distribution of the acyl chains linked to the diglucosamine backbone have a large tilt angle (> 45 degrees ) of the diglucosamine backbone with respect to the membrane surface, a conical molecular shape (larger cross-section of the hydrophobic than the hydrophilic moiety), and are endotoxically highly active. Monophosphoryl hexaacyl lipid A has a smaller tilt angle, and the conical shape is less expressed in favour of a more cylindrical shape. This correlates with decreasing endotoxic activity. Penta- and tetraacyl lipid A or hexaacyl lipid A with a symmetric acyl chain distribution (3/3) have a small tilt angle (< 25 degrees ) and a cylindrical shape and are endotoxically inactive, but may be antagonistic.
authors.affiliation: Research Center Borstel, Center for Medicine and Biosciences, Borstel, Germany. useydel@fz-borstel.de
authors.forename: U
authors.initials: U
authors.lastname: Seydel
authors.forename: M
authors.initials: M
authors.lastname: Oikawa
authors.forename: K
authors.initials: K
authors.lastname: Fukase
authors.forename: S
authors.initials: S
authors.lastname: Kusumoto
authors.forename: K
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D002236:Carbohydrate Conformation; D002861:Chromobacterium / Q000378:metabolism; D004731:Endotoxins / Q000737:chemistry / Q000502:physiology; D005454:Fluorescence Polarization; D008050:Lipid A / Q000737:chemistry* / Q000502:physiology*; D008956:Models, Chemical; D008962:Models, Theoretical; D016992:Rhodobacter / Q000378:metabolism; D013053:Spectrophotometry; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D004731:Endotoxins; D008050:Lipid A