Two-step activity-based protein profiling of diacylglycerol lipase

Org Biomol Chem. 2018 Jul 25;16(29):5250-5253. doi: 10.1039/c8ob01499j.

Abstract

Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator of neurotransmitter release. Chemical tools that visualize endogenous DAGL activity are desired. Here, we report the design, synthesis and application of a triazole urea probe for DAGL equipped with a norbornene as a biorthogonal handle. The activity and selectivity of the probe was assessed with activity-based protein profiling. This probe was potent against endogenous DAGLα (IC50 = 5 nM) and it was successfully applied as a two-step activity-based probe for labeling of DAGLα using an inverse electron-demand Diels-Alder ligation in living cells.

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Line, Tumor
  • Cycloaddition Reaction
  • Density Functional Theory
  • Endocannabinoids / chemistry
  • Humans
  • Lipoprotein Lipase / antagonists & inhibitors
  • Lipoprotein Lipase / chemistry*
  • Lipoprotein Lipase / metabolism*
  • Mice
  • Molecular Probes / chemistry
  • Molecular Probes / toxicity
  • Norbornanes / chemistry
  • Proteome
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Triazoles / chemistry
  • Urea / chemistry

Substances

  • Endocannabinoids
  • Molecular Probes
  • Norbornanes
  • Proteome
  • Recombinant Proteins
  • Triazoles
  • 2-norbornene
  • Urea
  • Lipoprotein Lipase