Halogenation-Dependent Effects of the Chlorosulfolipids of Ochromonas danica on Lipid Bilayers.
ACS chemical biology
The chlorosulfolipids are amphiphilic natural products with stereochemically complex patterns of chlorination and sulfation. Despite their role in toxic shellfish poisoning, potential pharmacological activities, and unknown biological roles, they remain understudied due to the difficulties in purifying them from natural sources. The structure of these molecules, with a charged sulfate group in the middle of the hydrophobic chain, appears incompatible with the conventional lipid bilayer structure. Questions about chlorosulfolipids remain unanswered partly due to the unavailability of structural analogues with which to conduct structure-function studies. We approach this problem by combining enantioselective total synthesis and membrane biophysics. Using a combination of Langmuir pressure-area isotherms of lipid monolayers, fluorescence imaging of vesicles, mass spectrometry imaging, natural product isolation, small-angle X-ray scattering, and cryogenic electron microscopy, we show that danicalipin A (1) likely inserts into lipid bilayers in the headgroup region and alters their structure and phase behavior. Specifically, danicalipin A (1) thins the bilayer and fluidizes it, allowing even saturated lipid to form fluid bilayers. Lipid monolayers show similar fluidizing upon insertion of danicalipin A (1). Furthermore, we show that the halogenation of the molecule is critical for its membrane activity, likely due to sterically controlled conformational changes. Synthetic unchlorinated and monochlorinated analogues do not thin and fluidize lipid bilayers to the same extent as the natural product. Overall, this study sheds light on how amphiphilic small molecules interact with lipid bilayers and the importance of stereochemistry and halogenation for this interaction.
View details for DOI 10.1021/acschembio.0c00624
View details for PubMedID 33035052
- CD22 blockade restores homeostatic microglial phagocytosis in ageing brains NATURE 2019; 568 (7751): 187-+
Ladderane phospholipids form a densely packed membrane with normal hydrazine and anomalously low proton/hydroxide permeability.
Proceedings of the National Academy of Sciences of the United States of America
Ladderane lipids are unique to anaerobic ammonium-oxidizing (anammox) bacteria and are enriched in the membrane of the anammoxosome, an organelle thought to compartmentalize the anammox process, which involves the toxic intermediate hydrazine (N2H4). Due to the slow growth rate of anammox bacteria and difficulty of isolating pure ladderane lipids, experimental evidence of the biological function of ladderanes is lacking. We have synthesized two natural and one unnatural ladderane phosphatidylcholine lipids and compared their thermotropic properties in self-assembled bilayers to distinguish between - and -ladderane function. We developed a hydrazine transmembrane diffusion assay using a water-soluble derivative of a hydrazine sensor and determined that ladderane membranes are as permeable to hydrazine as straight-chain lipid bilayers. However, pH equilibration across ladderane membranes occurs 5-10 times more slowly than across straight-chain lipid membranes. Langmuir monolayer analysis and the rates of fluorescence recovery after photobleaching suggest that dense ladderane packing may preclude formation of proton/hydroxide-conducting water wires. These data support the hypothesis that ladderanes prevent the breakdown of the proton motive force rather than blocking hydrazine transmembrane diffusion in anammox bacteria.
View details for PubMedID 30150407
Ladderane phospholipids form dense, low-polarity membranes with low proton/hydroxide permeability
AMER CHEMICAL SOC. 2018
View details for Web of Science ID 000447600003818
Ladderane Phospholipids Form Dense Membranes with Low Proton Permeability
CELL PRESS. 2018: 260A
View details for Web of Science ID 000430439600554
Chemical Synthesis and Self-Assembly of a Ladderane Phospholipid
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2016; 138 (49): 15845-15848
Ladderane lipids produced by anammox bacteria constitute some of the most structurally fascinating yet poorly studied molecules among biological membrane lipids. Slow growth of the producing organism and the inherent difficulty of purifying complex lipid mixtures have prohibited isolation of useful amounts of natural ladderane lipids. We have devised a highly selective total synthesis of ladderane lipid tails and a full phosphatidylcholine to enable biophysical studies on chemically homogeneous samples of these molecules. Additionally, we report the first proof of absolute configuration of a natural ladderane.
View details for DOI 10.1021/jacs.6b10706
View details for Web of Science ID 000389962800013
View details for PubMedID 27960308
View details for PubMedCentralID PMC5279923