Molecular basis of phospholipase A2 activity toward phospholipids with sn-1 substitutions |
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Authors: | Linderoth Lars Andresen Thomas L Jørgensen Kent Madsen Robert Peters Günther H |
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Institution: | * Department of Chemistry and Technical University of Denmark, Kgs. Lyngby, Denmark † LiPlasome Pharma A/S, Technical University of Denmark, Kgs. Lyngby, Denmark ‡ Risø National Laboratory, Technical University of Denmark, Roskilde, Denmark § Center for Sustainable and Green Chemistry; and Kgs. Lyngby, Denmark ¶ MEMPHYS-Center for Biomembrane Physics, Kgs. Lyngby, Denmark |
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Abstract: | We studied secretory phospholipase A2 type IIA (sPLA2) activity toward phospholipids that are derivatized in the sn-1 position of the glycerol backbone. We explored what type of side group (small versus bulky groups, hydrophobic versus polar groups) can be introduced at the sn-1 position of the glycerol backbone of glycerophospholipids and at the same time be hydrolyzed by sPLA2. The biophysical characterization revealed that the modified phospholipids can form multilamellar vesicles, and several of the synthesized sn-1 functionalized phospholipids were hydrolyzed by sPLA2. Molecular dynamics simulations provided detailed insight on an atomic level that can explain the observed sPLA2 activity toward the different phospholipid analogs. The simulations revealed that, depending on the nature of the side chain located at the sn-1 position, the group may interfere with an incoming water molecule that acts as the nucleophile in the enzymatic reaction. The simulation results are in agreement with the experimentally observed sPLA2 activity toward the different phospholipid analogs. |
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