Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2{Delta}) mutants is influenced by the carbon source and rapamycin.
Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2{Delta}) mutants is influenced by the carbon source and rapamycin.
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DOI：
10.1099/mic.0.034348-0
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
McCusker JH
中科院分区：
文献类型：
--
作者：
Kingsbury JM;McCusker JH
异亮氨酸和缬氨酸生物合成酶乙酰乳酸合成酶(ILV2P)是一种很有吸引力的抗真菌药物靶标，因为哺乳动物中不存在异亮氨酸和缬氨酸的生物合成途径，酿酒酵母ILV2Δ突变株不能在体内存活，新生隐球菌ILV2突变株是无毒的，酿酒酵母和新生葡萄球菌ILV2突变株都会在分离亮氨酸和缬氨酸饥饿后死亡。为了进一步探索ILV2P作为抗真菌药物靶点的潜力，我们破坏了白色念珠菌ILV2，并证明了白色念珠菌ILV2Δ突变体的毒力显著减弱，也是深度饥饿杀灭的，仅在异亮氨酸和缬氨酸饥饿4小时后，生存能力下降了100倍以上。由于杀菌饥饿将有利于药物设计，我们探索了酿酒酵母和白色念珠菌ilv2Δ突变体的饥饿-杀灭表型的基础。由于ILV1的突变是异亮氨酸生物合成的第一步所必需的，但不能抑制ILV2的Δ饥饿致死缺陷，因此这种致死表型不是由于α-酮丁酸积累所致。我们发现，单独饥饿异亮氨酸对白色念珠菌的危害比对酿酒酵母的危害更大，而在两个物种中，饥饿对Valine的危害比对异亮氨酸的危害更大。有趣的是，虽然TOR抑制剂雷帕霉素进一步降低了酿酒酵母ILV2Δ饥饿的活力，但它提高了白色念珠菌ILV1Δ和ILV2Δ的活力。此外，从饥饿中恢复依赖于酿酒酵母ilv2Δ突变体在恢复过程中存在的碳源，这使人想起异亮氨酸和Valine饥饿导致该物种处于可存活但不可培养的状态，而白色念珠菌ilv1Δ和ilv2Δ的活性受到饥饿期间存在的碳源的影响，这支持了葡萄糖消耗在白念珠菌杀灭表型中的作用。
The isoleucine and valine biosynthetic enzyme acetolactate synthase (Ilv2p) is an attractive antifungal drug target since the isoleucine and valine biosynthetic pathway is not present in mammals, Saccharomyces cerevisiae ilv2Δ mutants do not survive in vivo, Cryptococcus neoformans ilv2 mutants are avirulent, and both S. cerevisiae and C. neoformans ilv2 mutants die upon isoleucine and valine starvation. To further explore the potential of Ilv2p as an antifungal drug target, we disrupted Candida albicans ILV2, and demonstrated that C. albicans ilv2Δ mutants were significantly attenuated in virulence, and were also profoundly starvation-cidal, with a greater than 100-fold reduction in viability after only four hours of isoleucine and valine starvation. As fungicidal starvation would be advantageous for drug design, we explored the basis of the starvation-cidal phenotype in both S. cerevisiae and C. albicans ilv2Δ mutants. Since the mutation of ILV1, required for the first step of isoleucine biosynthesis, did not suppress the ilv2Δ starvation-cidal defects in either species, the cidal phenotype was not due to α–ketobutyrate accumulation. We found that starvation for isoleucine alone was more deleterious in C. albicans than S. cerevisiae, and starvation for valine was more deleterious than for isoleucine in both species. Interestingly, while the TOR inhibitor rapamycin further reduced S. cerevisiae ilv2Δ starvation viability, it increased C. albicans ilv1Δ and ilv2Δ viability. Furthermore, the recovery from starvation was dependent on the carbon source present during recovery for S. cerevisiae ilv2Δ mutants, reminiscent of isoleucine and valine starvation inducing a viable but nonculturable-like state in this species, while C. albicans ilv1Δ and ilv2Δ viability was influenced by the carbon source present during starvation, supporting a role for glucose wasting in the C. albicans cidal phenotype.
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影响因子：
4
作者：
Divol, B;Lonvaud-Funel, A
通讯作者：
Lonvaud-Funel, A
影响因子：
3.2
作者：
Epelbaum, S;Chipman, DM;Barak, Z
通讯作者：
Barak, Z
DOI：
10.1007/bf00269415
发表时间：
1975-01-01
期刊：
MOLECULAR & GENERAL GENETICS
影响因子：
--
作者：
HENRY, SA;DONAHUE, TF;CULBERTSON, MR
通讯作者：
CULBERTSON, MR
影响因子：
--
作者：
Kingsbury, JM;Yang, ZG;McCusker, JH
通讯作者：
McCusker, JH
影响因子：
7.4
作者：
LANDSTEIN, D;CHIPMAN, DM;BARAK, Z
通讯作者：
BARAK, Z