Singh Shubham, Dransfeld Ulrich, Ambaw Yohannes, Lopez-Scarim Joshua, Farese Robert V, Walther Tobias C
Cell Biology Program, Sloan Kettering Institute, MSKCC, New York, NY, USA.
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
bioRxiv. 2024 Mar 21:2024.03.21.586175. doi: 10.1101/2024.03.21.586175.
Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, in particular 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 ) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial -stereochemistry is achieved is unknown. Here we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal -BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction . 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 Alzheimer's disease risk, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal -BMP, a crucial lipid for maintaining brain health.
双（单酰甘油）磷酸酯（BMP）是一种丰富的溶酶体磷脂，是脂质尤其是神经节苷脂降解所必需的。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（而非R）立体构象中有两个手性甘油碳，使其免受溶酶体降解。这种不寻常但至关重要的S - 立体化学是如何实现的尚不清楚。在这里，我们报告磷脂酶D3和D4（PLD3和PLD4）合成溶酶体S - BMP，两种酶均可催化关键的甘油立体反转反应。在PLD3或PLD4高度表达的细胞或小鼠组织（PLD3在脑中；PLD4在脾中）中删除PLD3或PLD4会显著降低BMP水平，导致神经节苷脂贮积症和溶酶体异常。与神经退行性疾病相关的PLD3突变体，包括阿尔茨海默病风险，降低了PLD3的催化活性。我们得出结论，PLD3/4酶合成溶酶体S - BMP，这是维持大脑健康的关键脂质。
