EMAIL THIS PAGE TO A FRIEND

Nature chemical biology

DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses.


PMID 23103940

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLα and DAGLβ. Chemical probes to perturb DAGLs are needed to characterize endocannabinoid function in biological processes. Here we report a series of 1,2,3-triazole urea inhibitors, along with paired negative-control and activity-based probes, for the functional analysis of DAGLβ in living systems. Optimized inhibitors showed high selectivity for DAGLβ over other serine hydrolases, including DAGLα (∼60-fold selectivity), and the limited off-targets, such as ABHD6, were also inhibited by the negative-control probe. Using these agents and Daglb(-/-) mice, we show that DAGLβ inactivation lowers 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages in a manner that is distinct and complementary to disruption of cytosolic phospholipase-A2. We observed a corresponding reduction in lipopolysaccharide-induced tumor necrosis factor-α release. These findings indicate that DAGLβ is a key metabolic hub within a lipid network that regulates proinflammatory responses in macrophages.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SML1364
KT109, ≥98% (HPLC)
C27H26N4O
SML1688
KT172, ≥98% (HPLC)
C28H28N4O2
SML1308 KT195, ≥98% (HPLC)
C27H26N4O2