Thykaer Jette, Andersen Mikael R, Baker Scott E
Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Kgs Lyngby, Denmark.
Med Mycol. 2009;47 Suppl 1:S80-7. doi: 10.1080/13693780802455305. Epub 2009 Feb 27.
Computational metabolic flux modeling has been a great aid for both understanding and manipulating microbial metabolism. A previously developed metabolic flux model for Aspergillus niger, an economically important biotechnology fungus known for protein and organic acid production, is comprised of 1190 biochemically unique reactions that are associated with 871 open reading frames. Through a systematic in silico deletion of single metabolic reactions using this model, several essential metabolic pathways were identified for A. niger. A total of 138 reactions were identified as being essential biochemical reactions during growth on a minimal glucose medium. The majority of the reactions grouped into essential biochemical pathways covering cell wall biosynthesis, amino acid biosynthesis, energy metabolism and purine and pyrimidine metabolism. Based on the A. niger open reading frames associated with the reactions, we identified orthologous candidate essential genes in Aspergillus fumigatus. Our predictions are validated in part by the modes of action for some antifungal drugs and by molecular genetic studies of essential genes in A. fumigatus and other fungi. The use of metabolic models to predict essential reactions and pathways in Aspergillus spp. has promise to inform reverse genetic studies of gene essentiality and identify potential targets for antifungal development.
计算代谢通量建模对于理解和调控微生物代谢起到了很大的帮助作用。之前为黑曲霉开发的代谢通量模型，这是一种在生物技术领域具有重要经济价值、以生产蛋白质和有机酸而闻名的真菌，该模型由1190个具有生化独特性的反应组成，这些反应与871个开放阅读框相关联。利用这个模型通过系统地在计算机上删除单个代谢反应，为黑曲霉确定了几个必需的代谢途径。在以葡萄糖为唯一碳源的基本培养基上生长期间，总共138个反应被确定为必需的生化反应。大多数反应归为必需的生化途径，涵盖细胞壁生物合成、氨基酸生物合成、能量代谢以及嘌呤和嘧啶代谢。基于与这些反应相关的黑曲霉开放阅读框，我们在烟曲霉中鉴定出直系同源的候选必需基因。我们的预测在一定程度上通过某些抗真菌药物的作用模式以及对烟曲霉和其他真菌中必需基因的分子遗传学研究得到了验证。利用代谢模型预测曲霉属物种中的必需反应和途径，有望为基因必需性的反向遗传学研究提供信息，并确定抗真菌药物开发的潜在靶点。
