Each phospholipase A2 type exhibits distinct selectivity toward sn-1 ester, alkyl ether, and vinyl ether phospholipids

Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan;1867(1):159067. doi: 10.1016/j.bbalip.2021.159067. Epub 2021 Oct 9.


Glycerophospholipids are major components of cell membranes and have enormous variation in the composition of fatty acyl chains esterified on the sn-1 and sn-2 position as well as the polar head groups on the sn-3 position of the glycerol backbone. Phospholipase A2 (PLA2) enzymes constitute a superfamily of enzymes which play a critical role in metabolism and signal transduction by hydrolyzing the sn-2 acyl chains of glycerophospholipids. In human cell membranes, in addition to the conventional diester phospholipids, a significant amount is the sn-1 ether-linked phospholipids which play a critical role in numerous biological activities. However, precisely how PLA2s distinguish the sn-1 acyl chain linkage is not understood. In the present study, we expanded the technique of lipidomics to determine the unique in vitro specificity of three major human PLA2s, including Group IVA cytosolic cPLA2, Group VIA calcium-independent iPLA2, and Group V secreted sPLA2 toward the linkage at the sn-1 position. Interestingly, cPLA2 prefers sn-1 vinyl ether phospholipids known as plasmalogens over conventional ester phospholipids and the sn-1 alkyl ether phospholipids. iPLA2 showed similar activity toward vinyl ether and ester phospholipids at the sn-1 position. Surprisingly, sPLA2 preferred ester phospholipids over alkyl and vinyl ether phospholipids. By taking advantage of molecular dynamics simulations, we found that Trp30 in the sPLA2 active site dominates its specificity for diester phospholipids.

Keywords: Ether phospholipids; Lipidomics; Molecular dynamics simulation; Phospholipase A(2); Plasmalogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cytosol / metabolism
  • Glycerophospholipids / chemistry
  • Glycerophospholipids / metabolism
  • Humans
  • Hydrolysis
  • Kinetics
  • Phospholipases A2 / genetics*
  • Phospholipases A2 / metabolism
  • Phospholipid Ethers / metabolism*
  • Phospholipids / genetics*
  • Phospholipids / metabolism
  • Substrate Specificity / genetics
  • Vinyl Compounds / chemistry
  • Vinyl Compounds / metabolism*


  • Glycerophospholipids
  • Phospholipid Ethers
  • Phospholipids
  • Vinyl Compounds
  • vinyl ether
  • Phospholipases A2
  • Calcium