Protein depalmitoylases

Crit Rev Biochem Mol Biol. 2018 Feb;53(1):83-98. doi: 10.1080/10409238.2017.1409191. Epub 2017 Dec 14.


Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G protein depalmitoylases, yet later were shown to accept a number of S-palmitoylated protein and phospholipid substrates. Leveraging the development of isoform-selective APT inhibitors, several studies report distinct roles for APT enzymes in growth factor and hormonal signaling. Recent crystal structures of APT1 and APT2 reveal convergent acyl binding channels, suggesting additional factors beyond acyl chain recognition mediate substrate selection. In addition to APT enzymes, the ABHD17 family of hydrolases contributes to the depalmitoylation of Ras-family GTPases and synaptic proteins. Overall, enzymatic depalmitoylation ensures efficient membrane targeting by balancing the palmitoylation cycle, and may play additional roles in signaling, growth, and cell organization. In this review, we provide a perspective on the biochemical, structural, and cellular analysis of protein depalmitoylases, and outline opportunities for future studies of systems-wide analysis of protein depalmitoylation.

Keywords: Palmitoylation; inhibitor; post-translational modification; serine hydrolase; thioesterase.

Publication types

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

MeSH terms

  • Animals
  • Humans
  • Lipoylation*
  • Models, Molecular
  • Monoacylglycerol Lipases / chemistry
  • Monoacylglycerol Lipases / metabolism*
  • Protein Processing, Post-Translational*
  • Proteins / chemistry
  • Proteins / metabolism
  • Serine Proteases / chemistry
  • Serine Proteases / metabolism*
  • Thiolester Hydrolases / chemistry
  • Thiolester Hydrolases / metabolism*


  • Proteins
  • Monoacylglycerol Lipases
  • Thiolester Hydrolases
  • Serine Proteases