PDF(Pubmed)
Abstract：
Candida albicans is a commensal fungus, opportunistic pathogen, and the most common cause of fungal infection in humans. The biosynthesis of phosphatidylcholine (PC), a major eukaryotic glycerophospholipid, occurs through two primary pathways. In Saccharomyces cerevisiae and some plants, a third PC synthesis pathway, the PC deacylation/reacylation pathway (PC-DRP), has been characterized. PC-DRP begins with the acylation of the lipid turnover product, glycerophosphocholine (GPC), by the GPC acyltransferase, Gpc1, to form Lyso-PC. Lyso-PC is then acylated by lysolipid acyltransferase, Lpt1, to produce PC. Importantly, GPC, the substrate for Gpc1, is a ubiquitous metabolite available within the host. GPC is imported by C. albicans, and deletion of the major GPC transporter, Git3, leads to decreased virulence in a murine model. Here we report that GPC can be directly acylated in C. albicans by the protein product of orf19.988, a homolog of ScGpc1. Through lipidomic studies, we show loss of Gpc1 leads to a decrease in PC levels. This decrease occurs in the absence of exogenous GPC, indicating that the impact on PC levels may be greater in the human host where GPC is available. A gpc1Δ/Δ strain exhibits several sensitivities to antifungals that target lipid metabolism. Furthermore, loss of Gpc1 results in both a hyphal growth defect in embedded conditions and a decrease in long-term cell viability. These results demonstrate for the first time the importance of Gpc1 and this alternative PC biosynthesis route (PC-DRP) to the physiology of a pathogenic fungus.
摘要：
白色念珠菌是一种共生真菌，机会性病原体，也是人类真菌感染最常见的原因。磷脂酰胆碱（PC）的生物合成，一种主要的真核细胞甘油磷脂，通过两个主要途径发生。在酿酒酵母和一些植物中，第三种PC合成途径，PC脱酰/反应途径（PC-DRP），已被定性。PC-DRP从脂质周转产物的酰化开始，甘油磷酸胆碱（GPC），通过GPC酰基转移酶，Gpc1，形成Lyso-PC。然后通过溶血脂酰基转移酶酰化Lyso-PC，Lpt1，以产生PC。重要的是,GPC,Gpc1的底物是宿主中普遍存在的代谢产物。GPC由白色念珠菌进口，删除主要的GPC转运蛋白，Git3导致小鼠模型中的毒力降低。在这里，我们报道了GPC可以通过scGpc1的同源物orf19.988的蛋白质产物在白色念珠菌中直接酰化。通过脂质组学研究，我们显示Gpc1的丢失导致PC水平降低。这种减少发生在不存在外源GPC的情况下，这表明在GPC可用的人类宿主中对PC水平的影响可能更大。gpc1Δ/Δ菌株对靶向脂质代谢的抗真菌药具有多种敏感性。Further,Gpc1的丢失导致在嵌入条件下的菌丝生长缺陷，和长期细胞活力的下降。这些结果首次证明了Gpc1和这种替代PC生物合成途径（PC-DRP）对病原真菌生理学的重要性。
