A framework for application of metabolic modeling in yeast to predict the effects of nsSNV in human orthologs.
A framework for application of metabolic modeling in yeast to predict the effects of nsSNV in human orthologs.
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DOI：
10.1186/1745-6150-9-9
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发表时间：
2014-06-03
期刊：
影响因子：
5.5
通讯作者：
Mazumder R
中科院分区：
文献类型：
--
作者：
Dingerdissen H;Weaver DS;Karp PD;Pan Y;Simonyan V;Mazumder R
我们以前提出了一种蛋白质组分析功能残基变异的方法，其中我们确定了相应蛋白质活性部位残基中具有非同义单核苷酸变异(NsSNV)的所有人类基因集。其中34种蛋白质具有1：1：1的酶：途径：反应关系，通过创建和观察特定的酵母活性位点敲除和下游靶向代谢组学实验，使这些蛋白质成为实验室验证的理想候选。在这里，我们介绍了使用酵母代谢建模来预测由nsSNV导致的人类代谢行为的工作流程的下一步。对于先前确定的候选蛋白质，我们使用相互最佳的BLAST HITS方法，然后人工比对和路径比较，鉴定了6个适合通量平衡分析(FBA)的酵母同源蛋白。这些蛋白质中的5个已知与疾病有关，包括核糖5-磷酸异构酶缺乏症、肌病伴乳酸血症和铁粒母细胞贫血、谷胱甘肽代谢紊乱引起的贫血和两个卟啉症，我们怀疑第六个酶具有尚未根据本文描述的工作进行分类或了解的疾病关联。使用酵母7.0 FBA模型的初步发现表明，只有一种酶缺乏生长，但酵母7.0生物量功能的增强，以更好地模拟某些基因的敲除，表明另外三种蛋白质的变异具有生理相关性。因此，我们建议以下四种蛋白质用于实验室验证：Delta-氨基酮丙酸脱水酶、铁络合酶、核糖-5-磷酸异构酶和线粒体酪氨酰-tRNA合成酶。这项研究表明，随着更先进、更全面的模型的发展，该方法的预测能力将会提高。此外，这些发现将有助于开发简单的下游生化或质谱分析来证实这些预测，并检测某些已知的具有有害后果的nsSNV的存在。结果也可能有助于预测尚未很好地分类或注释的酶的活性部位nsSNV的未知结果。本文由Daniel Haft和Igor B.Rogozin撰写。
We have previously suggested a method for proteome wide analysis of variation at functional residues wherein we identified the set of all human genes with nonsynonymous single nucleotide variation (nsSNV) in the active site residue of the corresponding proteins. 34 of these proteins were shown to have a 1:1:1 enzyme:pathway:reaction relationship, making these proteins ideal candidates for laboratory validation through creation and observation of specific yeast active site knock-outs and downstream targeted metabolomics experiments. Here we present the next step in the workflow toward using yeast metabolic modeling to predict human metabolic behavior resulting from nsSNV. For the previously identified candidate proteins, we used the reciprocal best BLAST hits method followed by manual alignment and pathway comparison to identify 6 human proteins with yeast orthologs which were suitable for flux balance analysis (FBA). 5 of these proteins are known to be associated with diseases, including ribose 5-phosphate isomerase deficiency, myopathy with lactic acidosis and sideroblastic anaemia, anemia due to disorders of glutathione metabolism, and two porphyrias, and we suspect the sixth enzyme to have disease associations which are not yet classified or understood based on the work described herein. Preliminary findings using the Yeast 7.0 FBA model show lack of growth for only one enzyme, but augmentation of the Yeast 7.0 biomass function to better simulate knockout of certain genes suggested physiological relevance of variations in three additional proteins. Thus, we suggest the following four proteins for laboratory validation: delta-aminolevulinic acid dehydratase, ferrochelatase, ribose-5 phosphate isomerase and mitochondrial tyrosyl-tRNA synthetase. This study indicates that the predictive ability of this method will improve as more advanced, comprehensive models are developed. Moreover, these findings will be useful in the development of simple downstream biochemical or mass-spectrometric assays to corroborate these predictions and detect presence of certain known nsSNVs with deleterious outcomes. Results may also be useful in predicting as yet unknown outcomes of active site nsSNVs for enzymes that are not yet well classified or annotated. This article was reviewed by Daniel Haft and Igor B. Rogozin.
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影响因子：
14.9
作者：
Chatr-Aryamontri A;Breitkreutz BJ;Heinicke S;Boucher L;Winter A;Stark C;Nixon J;Ramage L;Kolas N;O'Donnell L;Reguly T;Breitkreutz A;Sellam A;Chen D;Chang C;Rust J;Livstone M;Oughtred R;Dolinski K;Tyers M
通讯作者：
Tyers M
影响因子：
--
作者：
Ewald, Jennifer Christina;Matta, Tanja;Zamboni, Nicola
通讯作者：
Zamboni, Nicola
影响因子：
4.5
作者：
Bonnefond, L;Frugier, M;Rudinger-Thirion, J
通讯作者：
Rudinger-Thirion, J
影响因子：
5.4
作者：
Aleem, Ansari M.;Wells, Leigh;Skrzypczak-Jankun, Ewa
通讯作者：
Skrzypczak-Jankun, Ewa
影响因子：
--
作者：
Heavner BD;Smallbone K;Barker B;Mendes P;Walker LP
通讯作者：
Walker LP