美国斯隆凯特琳学院Tobias C. Walther等研究人员合作发现，PLD3和PLD4合成S,S-BMP来促进溶酶体中的脂质降解。该研究于2024年10月17日在线发表于国际一流学术期刊《细胞》。

研究人员表示，双（单酰基甘油）磷酸（BMP）是一种丰富的溶酶体磷脂，必需于脂质（特别是神经节苷脂）的降解。BMP水平的改变与神经退行性疾病相关。与典型的甘油磷脂不同，溶酶体BMP在S（而不是R）立体构象中具有两个手性甘油碳，保护其免受溶酶体降解。这种不寻常但至关重要的S,S-立体化学是如何实现的尚不清楚。

研究人员发现，磷脂酶D3和D4（PLD3和PLD4）合成溶酶体S,S-BMP，任一酶都可以在体外催化关键的甘油立体反转反应。删除PLD3或PLD4显著降低了细胞或高表达这两种酶的鼠类组织（PLD3在大脑；PLD4在脾脏）的BMP水平，导致神经节苷脂症和溶酶体异常。与神经退行性疾病相关的PLD3突变体，包括阿尔茨海默病的风险，降低了PLD3的催化活性。

因此，研究人员认为，PLD3/4酶合成溶酶体S,S-BMP，这是一种维持大脑健康的重要脂质。

附：英文原文

Title: PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes

Author: Shubham Singh, Ulrich E. Dransfeld, Yohannes A. Ambaw, Joshua Lopez-Scarim, Robert V. Farese, Tobias C. Walther

Issue&Volume: 2024-10-17

Abstract: Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer’s disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.

DOI: 10.1016/j.cell.2024.09.036

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01094-8