24734-05-2Relevant academic research and scientific papers
Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases**
Arenz, Christoph,Basu, Shibom,Bechara, Cherine,Bossis, Guillaume,Cong, Xiaojing,Del Nero, Elise,Drapeau, Marion,Fontanel, Simon,Gabellier, Ludovic,Golebiowski, Jér?me,Granier, Sebastien,Healey, Robert D.,Hornemann, Thorsten,Jeannot, Sylvain,Karsai, Gergely,Leyrat, Cedric,Maurel, Damien,Saied, Essa M.,Saint-Paul, Julie
supporting information, (2021/12/09)
Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1-phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to revealing a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.
A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases
Li, Weiwei,Blankman, Jacqueline L.,Cravatt, Benjamin F.
, p. 9594 - 9595 (2008/02/13)
Hydrolytic enzymes constitute one of the largest and most diverse protein classes in Nature and play key roles in nearly all physiological and pathological processes. The mammalian serine hydrolase superfamily contains a remarkable number of uncharacterized members, with at least 40-50% of these enzymes lacking experimentally verified endogenous substrates and products. Assignment of metabolic and cellular functions to these enzymes requires the development of pharmacological tools to selectively perturb their activity. We describe herein a functional proteomic strategy to systematically develop potent and selective inhibitors for uncharacterized serine hydrolases and its application to the brain-enriched enzyme α/β-hydrolase-6. We anticipate that the methods described herein will facilitate the development of selective chemical probes to annotate the metabolic and (patho)physiological functions of many of the uncharacterized serine hydrolases that currently populate eukaryotic and prokaryotic proteomes. Copyright
