NAPE-PLD

Structural and functional insight into the biosynthesis of endogenous lipidic messengers by the N-Acyl Phosphatidylethanolamine Phospholipase D (NAPE-PLD)

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Longevity and healthy ageing are affected by our diet and lifestyle. EU-funded researchers have associated certain organic compounds called fatty acid ethanolamides (FAEs) with obesity and ageing.

Descrizione progetto (Article)

FAEs are important for nerve and metabolic regulation but the mechanisms involved in theirproduction and regulation are still unknown. Anandamide, for instance, is an FAE that stimulates appetite, addiction, and brain synaptogenesis.

Targeting the enzymes involved in FAE production could prove useful in treating inflammatory, pain, metabolic and neurodegenerative diseases.

The EU-funded project NAPE-PLD was initiated to unravel the molecular mechanisms involved in FAE synthesis. In addition, researchers will also investigate potential healthcare applications.

Researchers determined how an important enzyme in the process, N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) is localised in cells. The structure of NAPE-PLD was studied at the atomic level using state-of-the-art technology such as X Ray crystallography.

NAPEs are hormones released by the small intestine into our bloodstream when processing fats. This suggests that FAE synthesis is dependent on fat intake and this can also affect gastrointestinal motility, appetite, mood and anxiety. Regulating fat content in the diet could therefore be used to treat obesity, anorexia, addiction and mood disorders. Project members discovered several powerful molecules capable of modulating NAPE-PLD activity that could be used as therapeutic targets.

The findings of the NAPE-PLD project have immense potential in several medical fields including nutrition and medicine with significant implications for our health and welfare. Besides highlighting the importance of eating behaviour on good health and longevity, project outcomes have laid the foundation for future studies and development of innovative therapies.