A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function
A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function
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新型隐球菌中的葡聚糖合成酶 FKS1 同源物是单拷贝并编码基本功能
作者：
John R. Thompson;C. Douglas;Weili Li;C. K. Jue;B. Pramanik;Xiling Yuan;T. Rude;D. Toffaletti;J. Perfect;M. Kurtz
摘要隐球菌性脑膜炎是一种由新型隐球菌引起的真菌感染，在免疫功能低下的人群中普遍存在。这种疾病的治疗失败正在出现在临床上，通常与长期治疗现有的抗真菌药物。真菌细胞壁是药物治疗的有吸引力的靶点，因为细胞壁葡聚糖和几丁质的合成是哺乳动物细胞中不存在的过程。棘白菌素包括一类已知抑制1，3-β-葡聚糖合成的脂肽化合物，并且属于这类的至少两种化合物目前正在临床试验中作为对危及生命的真菌感染的治疗。对酿酒酵母和白色念珠菌突变体的研究发现，由FKS基因编码的葡聚糖合成酶的跨膜亚基是棘白菌素的分子靶点。在体外实验中，棘白菌素对念珠菌属和念珠菌属有较强的抗真菌活性，但对C.新人类为了研究C.由于新形线虫细胞对棘白菌素处理的敏感性较低，我们克隆了S.酿酒酵母FKS 1;新人类我们发展了一种评价隐球菌基因重要性的通用方法，并将其应用于FKS 1基因。该方法依赖于用质粒进行同源整合转化，该质粒可以在两个方向上整合，其中只有一个方向会破坏靶基因功能。分析结果表明，C.新生儿FKS 1基因是生存所必需的。梭neoformans的FKS 1序列与其他真菌的FKS 1序列密切相关，并且在C.新人类此外，已知在酵母菌中对棘白菌素敏感性至关重要的氨基酸残基在C. neoformans FKS 1序列。
ABSTRACT Cryptococcal meningitis is a fungal infection, caused byCryptococcus neoformans, which is prevalent in immunocompromised patient populations. Treatment failures of this disease are emerging in the clinic, usually associated with long-term treatment with existing antifungal agents. The fungal cell wall is an attractive target for drug therapy because the syntheses of cell wall glucan and chitin are processes that are absent in mammalian cells. Echinocandins comprise a class of lipopeptide compounds known to inhibit 1,3-β-glucan synthesis, and at least two compounds belonging to this class are currently in clinical trials as therapy for life-threatening fungal infections. Studies ofSaccharomyces cerevisiae and Candida albicansmutants identify the membrane-spanning subunit of glucan synthase, encoded by the FKS genes, as the molecular target of echinocandins. In vitro, the echinocandins show potent antifungal activity against Candida and Aspergillusspecies but are much less potent against C. neoformans. In order to examine why C. neoformans cells are less susceptible to echinocandin treatment, we have cloned a homolog of S. cerevisiae FKS1 from C. neoformans. We have developed a generalized method to evaluate the essentiality of genes inCryptococcus and applied it to the FKS1 gene. The method relies on homologous integrative transformation with a plasmid that can integrate in two orientations, only one of which will disrupt the target gene function. The results of this analysis suggest that the C. neoformans FKS1 gene is essential for viability. The C. neoformans FKS1 sequence is closely related to the FKS1 sequences from other fungal species and appears to be single copy in C. neoformans. Furthermore, amino acid residues known to be critical for echinocandin susceptibility in Saccharomyces are conserved in theC. neoformans FKS1 sequence.
拓扑异构酶 I 在新型隐球菌中至关重要：在病理学中发挥作用并作为抗真菌靶点。
影响因子：
3.3
作者：
DelPoeta,M;Toffaletti,DL;Rude,TH;Dykstra,CC;Heitman,J;Perfect,JR
通讯作者：
Perfect,JR
白色念珠菌磷酸核糖焦磷酸合成酶基因的表征。
DOI：
--
发表时间：
1997
期刊：
Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology.
影响因子：
--
作者：
Payne,T;Calderone,R
通讯作者：
Calderone,R
DOI：
10.1073/pnas.91.25.12008
发表时间：
1994-12-06
影响因子：
11.1
作者：
LODGE, JK;JACKSONMACHELSKI, E;GORDON, JI
通讯作者：
GORDON, JI