Global mass spectrometry based metabolomics profiling of erythrocytes infected with Plasmodium falciparum.
Global mass spectrometry based metabolomics profiling of erythrocytes infected with Plasmodium falciparum.
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DOI：
10.1371/journal.pone.0060840
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chang SP
中科院分区：
文献类型：
--
作者：
Sana TR;Gordon DB;Fischer SM;Tichy SE;Kitagawa N;Lai C;Gosnell WL;Chang SP
疟疾是一种全球性传染病，威胁着数百万人的生命。转录组学、蛋白质组学和功能基因组学研究，以及恶性疟原虫和智人基因组测序，为这种宿主-寄生虫关系提供了新的线索。最近在精确的质量测量质谱法、复杂的数据分析软件和生物途径数据库的可用性方面的进展已经汇聚在一起，以促进我们对体外恶性疟原虫感染（IRBC）和未感染（NRBC）红细胞的全球非靶向生化分析研究。为了扩大可检测代谢物的数量，我们优化了工作流程中的几个关键分析步骤。无针对性和有针对性的数据挖掘导致检测到超过1000个特征或化学实体。通过与METLIN代谢物数据库匹配注释非靶向特征。对于有针对性的数据挖掘，我们使用来自恶性疟原虫基因组代谢重建的化合物数据库查询数据。总共观察到超过150种差异注释代谢物。为了从我们的数据中证实已知生化途径的代表性，使用推断途径分析策略将注释的代谢物映射到BioCyc途径集合上。这种假设产生的方法导致许多代谢物在几个IRBC途径上的过度表达，最突出的是糖酵解。此外，“分支”TCA循环，部分尿素循环，核苷酸，氨基酸，分支酸，鞘脂和脂肪酸代谢的组件被发现在IRBC中改变。有趣的是，我们检测并证实了IRBC中环ADP核糖和磷酸核糖基AMP的水平升高，这是一种新的观察结果。这些代谢产物可能在恶性疟原虫感染过程中调节胞内Ca ~（2+）的释放。我们的研究结果支持通过非靶向数据采集进行全球代谢物分析的策略。非目标和目标数据挖掘工作流程在一起用于执行路径推断代谢组学时，具有避免对每个检测到的化合物进行MS/MS确认的益处。
Malaria is a global infectious disease that threatens the lives of millions of people. Transcriptomics, proteomics and functional genomics studies, as well as sequencing of the Plasmodium falciparum and Homo sapiens genomes, have shed new light on this host-parasite relationship. Recent advances in accurate mass measurement mass spectrometry, sophisticated data analysis software, and availability of biological pathway databases, have converged to facilitate our global, untargeted biochemical profiling study of in vitro P. falciparum-infected (IRBC) and uninfected (NRBC) erythrocytes. In order to expand the number of detectable metabolites, several key analytical steps in our workflows were optimized. Untargeted and targeted data mining resulted in detection of over one thousand features or chemical entities. Untargeted features were annotated via matching to the METLIN metabolite database. For targeted data mining, we queried the data using a compound database derived from a metabolic reconstruction of the P. falciparum genome. In total, over one hundred and fifty differential annotated metabolites were observed. To corroborate the representation of known biochemical pathways from our data, an inferential pathway analysis strategy was used to map annotated metabolites onto the BioCyc pathway collection. This hypothesis-generating approach resulted in over-representation of many metabolites onto several IRBC pathways, most prominently glycolysis. In addition, components of the “branched” TCA cycle, partial urea cycle, and nucleotide, amino acid, chorismate, sphingolipid and fatty acid metabolism were found to be altered in IRBCs. Interestingly, we detected and confirmed elevated levels for cyclic ADP ribose and phosphoribosyl AMP in IRBCs, a novel observation. These metabolites may play a role in regulating the release of intracellular Ca2+ during P. falciparum infection. Our results support a strategy of global metabolite profiling by untargeted data acquisition. Untargeted and targeted data mining workflows, when used together to perform pathway-inferred metabolomics, have the benefit of obviating MS/MS confirmation for every detected compound.
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