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Molecular Basis of Phospholipase A₂ Activity toward Phospholipids with sn-1 Substitutions

Lars Linderoth ^*, Thomas L. Andresen , Kent Jørgensen , Robert Madsen ^*  and Günther H. Peters ^* ¶

^* Department of Chemistry and 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 ^¶ MEMPHYS-Center for Biomembrane Physics, Kgs. Lyngby, Denmark

Correspondence: Address reprint requests to G. H. Peters, Dept. of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark. Tel.: 45-45252486; Fax: 45-45883136; E-mail: ghp{at}kemi.dtu.dk; or to T. L. Andresen, Risø National Laboratory, Technical University of Denmark, Roskilde, Denmark. Tel.: 45-46775480; Fax: 45-46774791; E-mail: thomas.andresen{at}risoe.dk.

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.