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

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

The endogenous Fatty Acid Ethanolamides (FAEs) are lipid signalling molecules emerging for their capacity to promote essential neurological, cytoprotective, and metabolic actions in mammalians. These molecules appear also coordinating nutrient status with obesity, and ultimately affect lifespan and ageing. Among these molecules, “anandamide” has potent anxiolytic and analgesic actions, and is able to stimulate appetite, addiction, and brain synaptogenesis, similarly to the well-known hyperphagic and neurological effects produced by marijuana and hashish. Other FAEs are involved in the modulation of the time frame between meals and inflammatory processes. However, despite the important roles mediated by the FAEs, little was known about the physiological and pathological stimuli that lead to their production in human, and about the mechanism and regulation of their biogenesis. The project “NAPE-PLD” focused on investigating the structural and molecular basis of the biogenesis of the FAEs, and exploring the possibility of targeting the enzyme that produces these important lipid messengers, named NAPE-PLD, for novel diagnostic and therapeutic perspectives in inflammation, metabolic disorders, and neurodegenerative diseases. The project was supported by a Marie Curie Action Grant [PIRG07-GA-2010-268385] to Dr Paola Magotti, under the supervision of Dr Gianpiero Garau, Project leader of Structural Biophysics at the Department of Drug Discovery of the Istituto Italiano di Tecnologia of Genoa (Italy, www.iit.it). Scientific results have been great and beyond expectation. Initially the researchers investigated the localization and trafficking of human NAPE-PLD in cells, and revealed where the biogenesis of the FAEs occurs. Later, they succeed to crystallize this membrane enzyme and determine its atomic structure at 2.6 Å resolution, taking advantage of the radiation generated by the European Synchrotron Radiation Facility (ESRF) of Grenoble (France), the most powerful source of X-rays in Europe (www.esrf.eu‎). The structure of NAPE-PLD revealed the molecular architecture of this enzyme, a functional protein homodimer having an unusual internal channel. The structure showed also how the enzyme associates to cell membranes, and the chemical details of the molecular mechanism that promotes the biosynthesis of FAEs. Structural analysis and other experiments allowed the researchers to unveil that the activity of NAPE-PLD is modulated by the physiological process of fat digestion in the gut. Hence, the biogenesis of lipid amide signals and their effects on gastrointestinal motility, appetite, mood and anxiety, result directly linked to the fat content of foods (Magotti et al, submitted). The discovery that human endogenous cannabinoids and analogue bioactive molecules are produced upon stimuli of fat foods has important therapeutic perspectives for obesity, anorexia, and other metabolic disorders. For example, it suggests how a high-fat diet might be associated in obese people to addiction-like behavior; how people might modulate stress and anxiety by eating foods that have a right content of fat; or how an infant might be encouraged to drink milk by its content of fat. Finally, the project led to the discovery of first potent molecular modulators of NAPE-PLD activity, which are now being evaluated for possible therapeutic uses as drugs. The impact of the results of the NAPE-PLD project is expected to be simply awesome. Findings have the potential to foster a series of future studies and applications in various fields of nutrition, physiology and medicine, which will be extremely relevant for both the scientific and medical community of the EU, and will have important socio-economic implications. Overall, the project shines a light on how eating behavior in humans is influenced by an appropriate amount of fat in food. For inquiries, please visit: http://www.iit.it/en/people/gianpiero-garau.html

Data: CORDIS, © European Union