Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases

J Lipid Res. 2012 Jan;53(1):43-50. doi: 10.1194/jlr.M019851. Epub 2011 Nov 3.


Sequence homology indicates the existence of three human cytosolic acyl protein thioesterases, including APT1 that is known to depalmitoylate H- and N-Ras. One of them is the lysophospholipase-like 1 (LYPLAL1) protein that on the one hand is predicted to be closely related to APT1 but on the other hand might also function as a potential triacylglycerol lipase involved in obesity. However, its role remained unclear. The 1.7 Å crystal structure of LYPLAL1 reveals a fold very similar to APT1, as expected, but features a shape of the active site that precludes binding of long-chain substrates. Biochemical data demonstrate that LYPLAL1 exhibits neither phospholipase nor triacylglycerol lipase activity, but rather accepts short-chain substrates. Furthermore, extensive screening efforts using chemical array technique revealed a first small molecule inhibitor of LYPLAL1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Humans
  • Lipase / metabolism
  • Lysophospholipase / antagonists & inhibitors
  • Lysophospholipase / chemistry*
  • Lysophospholipase / metabolism
  • Models, Molecular
  • Phospholipases / metabolism
  • Substrate Specificity


  • Phospholipases
  • Lipase
  • Lysophospholipase
  • LYPLAL1 protein, human