Designing New Natural‐Mimetic Phosphatidic Acid: A Versatile and Innovative Synthetic Strategy for Glycerophospholipid Research

We report the role of the fatty acyl chains in biological activities of phosphatidic acids (PA). Several PA probes having two different fatty acyl chains were synthesized through a multi-steps synthesis and bearing various fluorophores or photo-cross-linkers (PCL). We demonstrate that our probes maintain the biological activities of the natural PA, then we found hundreds of new proteins interacting with PA in function of their chain compositions.

Abstract

Glycerophospholipids (GPLs) play important roles in cellular compartmentalization and signaling. Among them, phosphatidic acids (PA) exist as many distinct species depending on acyl chain composition, each one potentially displaying unique signaling function. Although the signaling functions of PA have already been demonstrated in multiple cellular processes, the specific roles of individual PA species remain obscure due to a lack of appropriate tools. Indeed, current synthetic PA analogues fail to preserve all the functions of natural PA. To circumvent these limitations, we developed a novel synthetic approach to produce PA analogues without compromising structural integrity of acyl chains. Moreover, addition of a clickable moiety allowed flexible grafting of different molecules to PA analogues for various biological applications. Hence, this innovation also provides powerful tools to investigate specific biological activities of individual PA species, with potential applications in unraveling complex GPL-mediated signaling pathways.

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