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.

中文翻译：

---

PLD3 和 PLD4 合成 S，S-BMP，S-BMP 是一种关键的磷脂，可在溶酶体中进行脂质降解


双（单酰基甘油）磷酸盐 （BMP） 是一种丰富的溶酶体磷脂，是脂质降解所必需的，尤其是神经节苷脂。BMP 水平的改变与神经退行性疾病有关。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。在这里，我们报道了磷脂酶 D3 和 D4 （PLD3 和 PLD4） 合成溶酶体 S，S-BMP，其中任何一种酶在体外催化关键的甘油立体反转反应 。PLD3 或 PLD4 缺失显著降低了其中一种酶高度表达的细胞或小鼠组织中的 BMP 水平（PLD3 为大脑;PLD4 为脾脏），导致神经节苷脂沉积症和溶酶体异常。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 催化活性。我们得出结论，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。