title: [How independent pharmacological screenings in plants and humans led to the discovery of a new family of lipid metabolism inhibitors].
abstract: In eukaryotic cells, phosphatidic acid (PA) and diacylglycerol (DAG), are at the origin of all membrane glycerolipids. Their interconversion is achieved by dephosphorylation of PA and phosphorylation of DAG: they form therefore a metabolic hub. PA and DAG are also known to be versatile signaling molecules. Two independent pharmacological screenings conducted on plant and human targets, led to the discovery of a new family of compounds acting on enzymes binding to either PA or DAG, in biological contexts that seemed initially independent. On the one hand, in plants, monogalactosyldiacylglycerol synthases (MGDG synthases or MGD) are responsible for the synthesis of MGDG, which is the most profuse lipid of photosynthetic membranes, and thus essential for metabolism and development. MGD use DAG as substrate. On the other hand, in mammals, phospholipases D (PLD), that produce PA, are involved in a variety of signaling cascades that control a broad spectrum of cellular functions, and play a role in the development of cancers. The two independent pharmacological screenings described in this review aimed to identify inhibitory molecules of either MGD of the plant model Arabidopsis, or human PLD. In both cases, the obtained molecules are piperidinyl-benzimidazolone derivatives, thereby allowing to propose this family of molecules as a novel source of inspiration for the search of compounds interfering with glycerolipid metabolism, that could be useful for other biological and therapeutics contexts.
authors: Laboratoire de physiologie cellulaire végétale, UMR 5168, CNRS-CEA-INRA-université Grenoble Alpes, 17 rue des Martyrs, 38054 Grenoble Cedex, France.
authors: Florian
authors: F
authors: Chevalier
authors: Laboratoire de physiologie cellulaire végétale, UMR 5168, CNRS-CEA-INRA-université Grenoble Alpes, 17 rue des Martyrs, 38054 Grenoble Cedex, France.
authors: Éric
authors: É
authors: Maréchal
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000302:isolation & purification*; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors; D005989:Glycerides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D062069:Inventions; D050356:Lipid Metabolism / Q000187:drug effects*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D010944:Plants
chemical_list: D004791:Enzyme Inhibitors; D005989:Glycerides; D005700:Galactosyltransferases; C109990:1,2-diacylglycerol 3-beta-galactosyltransferase; D010739:Phospholipase D