Structural and functional insight into the biosynthesis of endogenous lipidic messengers by the N-Acyl Phosphatidylethanolamine Phospholipase D
Imbalances of human major lipid signaling pathways contribute to progression in inflammation, neurodegenerative and metabolic diseases. Among lipidic messengers, the family of bioactive N-Acylethanolamines (NAEs) is agonist at cannabinoid and nuclear α-type peroxisome proliferator-activated receptors. The ability of NAEs and their metabolic enzymes to modulate neurotransmission and a variety of pathophysiological processes, including inflammation, appetite, pain and mood, provides unique chances for drug discovery. Upon stimulation, bioactive NAEs are generated from cell membranes in a two-step pathway, which involves an N-acyltransferase and an N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD). NAEs bearing saturated and monounsaturated long acyl chains are significantly decreased in NAPE-PLD(-/-) mice suggesting this enzymes as key regulators of the NAE-mediated signaling potential. Very little is known about the molecular architecture of NAPE-PLD and the specific functional role of its N- and C-terminal domains. If given a chance, I will study domain trafficking in activated cells and to solve the X-ray structure of this membrane-bound protein. I will characterize the thermodynamics and kinetics of enzyme interactions, which are essential in understanding how NAPE-PLD
synthesizes NEAs and controls their cellular level. Findings will be used for a rational approach in the design of potent and selective NAPE-PLD ligands, which can be exploited pharmacologically to modulate the level of NAEs in inflammation, pain, and neurodegenerative disorders. These aims are a common goal of cell biology, structural biology, pharmacology, and medicinal chemistry, which could give an invaluable blueprint for the design of selective inhibitors, thus strongly impacting both EU scientific research and EU molecular medicine. The Drug Discovery and Development Unit of the Italian Institute of Technology is a unique working environment for their achievement.
Project budget 75.000,00
For further information please contact
Gianpiero Garau (D3 Department)