Phosphatidylserine synthase and phosphatidylserine decarboxylase are essential for cell wall integrity and virulence in Candida albicans
Phosphatidylserine synthase and phosphatidylserine decarboxylase are essential for cell wall integrity and virulence in Candida albicans
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DOI：
10.1111/j.1365-2958.2009.07018.x
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发表时间：
2010-03-01
影响因子：
3.6
通讯作者：
Reynolds, Todd B.
中科院分区：
文献类型：
--
作者：
Chen, Ying-Lien;Montedonico, Anthony E.;Reynolds, Todd B.
磷脂生物合成途径在几种病原体的毒力中起着至关重要的作用;然而，关于磷脂合成如何影响真菌（如白色念珠菌）的致病机制却知之甚少。梭白色念珠菌磷脂酰丝氨酸（PS）合酶突变体cho 1 Delta/Delta缺乏PS，具有降低的磷脂酰乙醇胺（PE），并且在全身性念珠菌病的小鼠模型中无毒力。cho 1 Delta/Delta突变体在细胞壁完整性、线粒体功能、丝状生长方面表现出缺陷，并且是乙醇胺营养缺陷型。PS是PE从头生物合成的前体。psd 1 Delta/Delta psd 2 Delta/Delta双突变体缺乏在从头途径中将PS转化为PE的PS脱羧酶，与cho 1 Delta/Delta突变体一样，其PE水平降低。psd 1 Delta/Delta psd 2 Delta/Delta突变体表现出与cho 1 Delta/Delta突变体相似的表型;然而，它的毒性稍强，细胞壁缺陷较少。cho 1 Delta/Delta和psd 1 Delta/Delta psd 2 Delta/Delta突变体表现出的毒力损失似乎与它们的细胞壁缺陷有关，这是由于从头PE生物合成的损失，但PS本身的损失加剧了这种缺陷。Cho 1 p在真菌中是保守的，而在哺乳动物中不存在，因此真菌PS合成酶是一个潜在的抗真菌药物新靶点。
P>Phospholipid biosynthetic pathways play crucial roles in the virulence of several pathogens; however, little is known about how phospholipid synthesis affects pathogenesis in fungi such as Candida albicans. A C. albicans phosphatidylserine (PS) synthase mutant, cho1 Delta/Delta, lacks PS, has decreased phosphatidylethanolamine (PE), and is avirulent in a mouse model of systemic candidiasis. The cho1 Delta/Delta mutant exhibits defects in cell wall integrity, mitochondrial function, filamentous growth, and is auxotrophic for ethanolamine. PS is a precursor for de novo PE biosynthesis. A psd1 Delta/Delta psd2 Delta/Delta double mutant, which lacks the PS decarboxylase enzymes that convert PS to PE in the de novo pathway, has diminished PE levels like those of the cho1 Delta/Delta mutant. The psd1 Delta/Delta psd2 Delta/Delta mutant exhibits phenotypes similar to those of the cho1 Delta/Delta mutant; however, it is slightly more virulent and has less of a cell wall defect. The virulence losses exhibited by the cho1 Delta/Delta and psd1 Delta/Delta psd2 Delta/Delta mutants appear to be related to their cell wall defects which are due to loss of de novo PE biosynthesis, but are exacerbated by loss of PS itself. Cho1p is conserved in fungi, but not mammals, so fungal PS synthase is a potential novel antifungal drug target.