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A biosynthetic pathway for anandamide

机译：Anandamide的生物合成途径

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摘要

The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released "on demand" by neurons in the brain. Anandamide is also generated by macro-phages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE-PLD). Here we document a biosynthetic pathway for anandamide in mouse brain and RAW264.7 macrophages that involves the phospholipase C (PLC)-catalyzed cleavage of NAPE to generate a lipid, phospho-anandamide, which is subsequently dephosphorylated by phos-phatases, including PTPN22, previously described as a protein tyrosine phosphatase. Bacterial endotoxin (LPS)-induced synthesis of anandamide in macrophages is mediated exclusively by the PLC/phosphatase pathway, which is up-regulated by LPS, whereas NAPE-PLD is down-regulated by LPS and functions as a salvage pathway of anandamide synthesis when the PLC/phosphatase pathway is compromised. Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC/phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target.
机译：内源性大麻素花生四烯酰乙醇胺（anandamide）是一种脂质递质，由大脑中的神经元“按需”合成和释放。 Anandamide也由巨噬细胞产生，其内毒素（LPS）诱导的合成与败血性休克和晚期肝硬化的低血压有关。可以通过其膜前体N-花生四烯酰基磷脂酰乙醇胺（NAPE）通过磷脂酶D（NAPE-PLD）的裂解来生成花and酰胺。在这里，我们记录了老鼠大脑和RAW264.7巨噬细胞中花生四烯酸酰胺的生物合成途径，该途径涉及磷脂酶C（PLC）催化的NAPE裂解，从而生成脂质磷酰花生四烯酸，随后被磷酸酯酶（包括PTPN22）去磷酸化，以前被称为蛋白质酪氨酸磷酸酶。细菌内毒素（LPS）诱导巨噬细胞中的anandamide合成仅由PLC /磷酸酶途径介导，而PLC /磷酸酶途径被LPS上调，而NAPE-PLD被LPS下调，并在以下情况下起anandamide合成的挽救途径PLC /磷酸酶途径受到损害。 PTPN22和内源性大麻素均与自身免疫性疾病有关，这表明Anandamide合成的PLC /磷酸酶途径可能是药物治疗的靶标。

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