Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity

Citation
U. Seydel et al., Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity, EUR J BIOCH, 267(10), 2000, pp. 3032-3039
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
EUROPEAN JOURNAL OF BIOCHEMISTRY
ISSN journal
0014-2956 → ACNP
Volume
267
Issue
10
Year of publication
2000
Pages
3032 - 3039
Database
ISI
SICI code
0014-2956(200005)267:10<3032:ICOLAI>2.0.ZU;2-1
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, exhi bits a peculiar chemical structure, harbours the 'endotoxic principle' of L PS and is also responsible for the expression of pathophysiological effects . Chemically modified lipid A can be endotoxically inactive, but may expres s strong antagonistic activity against endotoxically active LPS. By applyin g orientation measurements with attenuated total reflectance (ATR) infrared spectroscopy on hydrated lipid A samples, we show here that these differen t biological activities are directly correlated to the intrinsic conformati on 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 r espect to the membrane surface, a conical molecular shape (larger cross-sec tion of the hydrophobic than the hydrophilic moiety), and are endotoxically highly active. Monophosphoryl hexaacyl lipid A has a smaller tilt angle, a nd the conical shape is less expressed in favour of a more cylindrical shap e. 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 end otoxically inactive, but may be antagonistic.