Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
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DOI：
10.1038/msb.2008.15
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发表时间：
2008-03-01
影响因子：
9.9
通讯作者：
Papin, Jason A.
中科院分区：
文献类型：
--
作者：
Chavali, Arvind K.;Whittemore, Jeffrey D.;Papin, Jason A.
系统分析促进了多种生物体代谢网络的表征。我们重建了大型利什曼原虫的代谢网络，这是一种特征不明的生物体，可在哺乳动物宿主中引起皮肤利什曼病。该网络重建包含 560 个基因、1112 个反应、1101 个代谢物和 8 个独特的亚细胞定位。使用基于系统的方法，我们假设了一套全面的致命单基因和双基因删除，其中一些使用已发表的数据进行了验证，准确率约为 70%。此外，我们对 L.major 基因组中数十个以前未表征的基因进行了假设注释，并提出了一种基本的生长培养基。我们通过两个概念验证示例进一步证明了网络重建的实用性，这些示例使我们深入了解了在存在酶抑制剂的情况下网络的鲁棒性，并描述了前鞭毛体/无鞭毛体阶段特异性代谢。对 L. Major 的这种重建和相关网络分析对于原生动物来说是首次。它可以作为澄清数据源之间差异、生成可通过实验验证的假设并确定理想治疗靶点的工具。
Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems-based approach, we hypothesized a comprehensive set of lethal single and double gene deletions, some of which were validated using published data with approximately 70% accuracy. Additionally, we generated hypothetical annotations to dozens of previously uncharacterized genes in the L. major genome and proposed a minimal medium for growth. We further demonstrated the utility of a network reconstruction with two proof-of-concept examples that yielded insight into robustness of the network in the presence of enzymatic inhibitors and delineation of promastigote/amastigote stage-specific metabolism. This reconstruction and the associated network analyses of L. major is the first of its kind for a protozoan. It can serve as a tool for clarifying discrepancies between data sources, generating hypotheses that can be experimentally validated and identifying ideal therapeutic targets.