Gründling Angelika, Brogan Anna P, James Michael J, Ramirez-Guadiana Fernando H, Roney Ian J, Bernhardt Thomas G, Rudner David Z
Section of Molecular Microbiology and Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, United Kingdom.
Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2418775122. doi: 10.1073/pnas.2418775122. Epub 2025 Jan 27.
The cytoplasmic membrane of bacteria is composed of a phospholipid bilayer made up of a diverse set of lipids. Phosphatidylglycerol (PG) is one of the principal constituents and its production is essential for growth in many bacteria. All the enzymes required for PG biogenesis in have been identified and characterized decades ago. However, it has remained poorly understood how gram-positive bacteria perform the terminal step in the pathway that produces this essential lipid. In this reaction is mediated by three functionally redundant phosphatases that convert phosphatidylglycerophosphate (PGP) into PG. Here, we show that homologs of these enzymes in are not required for PG synthesis. Instead, we identified a previously uncharacterized protein, YqeG (renamed PgpP), as an essential enzyme required for the conversion of PGP into PG. Expression of or PgpP in lacking all three Pgp enzymes supported the growth of the strain. Furthermore, depletion of PgpP in led to growth arrest, reduced membrane lipid staining, and accumulation of PGP. PgpP is broadly conserved among Firmicutes and Cyanobacteria. Homologs are also present in yeast mitochondria and plant chloroplasts, suggesting that this widely distributed enzyme has an ancient origin. Finally, evidence suggests that PgpP homologs are essential in many gram-positive pathogens and thus the enzyme represents an attractive target for antibiotic development.
细菌的细胞质膜由多种脂质组成的磷脂双分子层构成。磷脂酰甘油（PG）是主要成分之一，其合成对于许多细菌的生长至关重要。几十年前就已鉴定并表征了PG生物合成所需的所有酶。然而，革兰氏阳性菌如何完成产生这种必需脂质的途径中的末端步骤仍知之甚少。在大肠杆菌中，该反应由三种功能冗余的磷酸酶介导，它们将磷脂酰甘油磷酸（PGP）转化为PG。在这里，我们表明这些酶在枯草芽孢杆菌中的同源物对于PG合成不是必需的。相反，我们鉴定出一种先前未表征的枯草芽孢杆菌蛋白YqeG（重新命名为PgpP），它是将PGP转化为PG所需的必需酶。在缺乏所有三种Pgp酶的枯草芽孢杆菌中表达大肠杆菌或嗜热栖热菌的PgpP支持了该菌株的生长。此外，枯草芽孢杆菌中PgpP的缺失导致生长停滞、膜脂染色减少和PGP积累。PgpP在厚壁菌门和蓝细菌中广泛保守。在酵母线粒体和植物叶绿体中也存在同源物，这表明这种广泛分布的酶具有古老的起源。最后，有证据表明PgpP同源物在许多革兰氏阳性病原体中是必需的，因此该酶是抗生素开发的一个有吸引力的靶点。
