Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis.
Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis.
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DOI：
10.1186/1752-0509-4-120
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发表时间：
2010-08-31
影响因子：
--
通讯作者：
Holzhütter HG
中科院分区：
文献类型：
--
作者：
Huthmacher C;Hoppe A;Bulik S;Holzhütter HG
尽管为防治疟疾作出了巨大努力，但每年仍有多达5亿人受到疟疾的折磨，其中100多万人死亡。目前还没有批准的疫苗，抗疟药的抗药性广泛传播。因此，迫切需要新的抗疟疾药物。在这里，我们提出了一个计算分析的恶性疟原虫，最致命的疟疾病原体的代谢。我们组装了一个区室化的代谢模型，并预测生命周期阶段的特定代谢的通量平衡的方法，整合基因表达数据的帮助下。寄生虫和宿主之间的预测代谢物交换被认为是在良好的实验结果符合寄生虫的代谢网络嵌入到其主机（红细胞）。敲除模拟确定了寄生虫内307个不可或缺的代谢反应。在57种实验证明的必需酶中，回收了35种，另外还回收了16种酶，如果另外假设从宿主细胞中摄取的营养物是有限的，并且被抑制的酶催化的所有反应都被阻断的话。这组预测的推定的药物靶点，显示富含至少2.75倍的真实靶点，进一步分析了与人类酶的同源性，与其他生物体中治疗靶点的功能相似性及其预防和疾病治疗的预测效力。结果表明，我们的通量平衡方法预测的一组必需酶代表了进一步药物开发的一个有希望的起点。
Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte). Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.
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影响因子：
9.9
作者：
Andersen, Mikael Rordam;Nielsen, Michael Lynge;Nielsen, Jens
通讯作者：
Nielsen, Jens
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
DOI：
10.1073/pnas.86.2.651
发表时间：
1989-01-01
影响因子：
11.1
作者：
BITONTI, AJ;DUMONT, JA;SJOERDSMA, A
通讯作者：
SJOERDSMA, A
影响因子：
4.8
作者：
Chakrabarti, D;Da Silva, T;Allen, CM
通讯作者：
Allen, CM
影响因子：
4.9
作者：
Choubey, Vinay;Maity, Pallab;Bandyopadhyay, Uday
通讯作者：
Bandyopadhyay, Uday