美国斯坦福大学Monther Abu-Remaileh团队近期取得重要工作进展，他们研究发现巴藤病基因产物CLN5是溶酶体二（单酰基甘油）磷酸盐合酶。相关研究成果2023年9月15日在线发表于《科学》杂志上。

据介绍，溶酶体严重依赖二（单酰基甘油）磷酸盐（BMP）来刺激脂质分解代谢、胆固醇稳态和溶酶体功能。单基因和复杂神经退行性疾病中BMP水平的变化表明其在人类健康中具有重要功能。然而，BMP合成的位点和机制几十年来一直存在争议。

研究人员发现，巴藤病基因产物CLN5是一种难以捉摸的BMP合酶（BMPS）。BMPS缺陷的细胞表现出BMP合成前体溶血磷脂酰甘油（LPG）大量积累、BMP种类的丢失以及脂质代谢功能障碍。在机理上，研究发现BMPS介导的合成是通过两个LPG分子之间不依赖能量的碱交换反应进行的，并且对负载BMP的囊泡活性增加。

总之，这一研究阐明了BMP的生物合成，并揭示了晚期核内体/溶酶体的合成代谢功能。

附：英文全文

Author: Uche N. Medoh, Andy Hims, Julie Y. Chen, Ali Ghoochani, Kwamina Nyame, Wentao Dong, Monther Abu-Remaileh

Issue&Volume: 2023-09-15

Abstract: Lysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels in monogenic and complex neurodegeneration suggest an essential function in human health. However, the site and mechanism responsible for BMP synthesis have been subject to debate for decades. Here, we report that the Batten disease gene product CLN5 is the elusive BMP synthase (BMPS). BMPS-deficient cells exhibited a massive accumulation of the BMP synthesis precursor lysophosphatidylglycerol (LPG), depletion of BMP species, and dysfunctional lipid metabolism. Mechanistically, we found that BMPS mediated synthesis through an energy-independent base exchange reaction between two LPG molecules with increased activity on BMP-laden vesicles. Our study elucidates BMP biosynthesis and reveals an anabolic function of late endosomes/lysosomes.

DOI: adg9288

Source: https://www.science.org/doi/10.1126/science.adg9288