Candida albicans phosphate transport, facilitating nucleotide sugar biosynthesis, contributes to cell wall stability.
Candida albicans phosphate transport, facilitating nucleotide sugar biosynthesis, contributes to cell wall stability.
复制标题
白色念珠菌磷酸盐转运，促进核苷酸糖生物合成，有助于细胞壁稳定性。
DOI：
10.1099/acmi.cc2021.po0036
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发表时间：
2021
影响因子：
--
通讯作者：
Acosta-Zaldivar M
中科院分区：
文献类型：
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作者：
Acosta-Zaldivar M
白色念珠菌高亲和磷酸转运蛋白Pho84是雷帕霉素信号转导、氧化应激抗性和毒力的正常靶标所必需的。它还有助于白色念珠菌对两种抗真菌药物的耐受性，多烯类和棘白菌素。棘白菌素抑制主要细胞壁成分β -1,3-葡聚糖的生物合成。缺乏Pho84的细胞对棘白菌素暴露以外的其他形式的细胞壁应激敏感，而它们的细胞壁完整性信号反应较弱。代谢组学实验表明，与从磷酸盐饥饿中恢复的野生型细胞相比，pho84突变体中磷酸中间体（包括核苷酸如ATP和核苷酸糖）的水平较低。非磷前体如核碱基和核苷升高。外细胞壁磷酸甘露聚糖的生物合成需要一种核苷酸糖，甘露糖。核苷酸糖udp -葡萄糖是合成两种主要结构细胞壁多糖-1,3-和-1,6-葡聚糖的酶的底物。另一种核苷酸糖，udp - n -乙酰氨基葡萄糖，是几丁质合成酶的底物，它产生细胞间隔和侧细胞壁的稳定成分。Pho84活性的缺乏和磷酸盐饥饿，增强了这些酶的药理学或遗传扰动。我们的模型是低底物浓度的β - d -葡聚糖和几丁质合成酶降低酶促反应速率和增强药物抑制剂，以降低其细胞壁稳定产物的产量。磷酸盐的输入在真菌和人类细胞之间并不保守，人类也不合成β - d -葡聚糖或几丁质。因此，同时抑制这些过程可以产生对人体低毒性的有效抗真菌作用。
The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin signaling, oxidative stress resistance and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild type cells recovering from phosphate starvation. Non-phosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar,GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. Our model is that low substrate concentrations of beta-D-glucan- and chitin synthases diminish enzymatic reaction rates and potentiate pharmacologic inhibitors to decrease the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-D-glucans or chitin. Hence inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans.