Kovács Szabolcs Cselgő, Szappanos Balázs, Tengölics Roland, Notebaart Richard A, Papp Balázs
HCEMM-BRC Metabolic Systems Biology Lab, Szeged, Hungary.
Biological Research Centre, Institute of Biochemistry, Synthetic and Systems Biology Unit, Eötvös Loránd Research Network (ELKH), Szeged, Hungary.
Bioinformatics. 2022 May 26;38(11):3070-3077. doi: 10.1093/bioinformatics/btac282.
Bioproduction of value-added compounds is frequently achieved by utilizing enzymes from other species. However, expression of such heterologous enzymes can be detrimental due to unexpected interactions within the host cell. Recently, an alternative strategy emerged, which relies on recruiting side activities of host enzymes to establish new biosynthetic pathways. Although such low-level 'underground' enzyme activities are prevalent, it remains poorly explored whether they may serve as an important reservoir for pathway engineering.
Here, we use genome-scale modeling to estimate the theoretical potential of underground reactions for engineering novel biosynthetic pathways in Escherichia coli. We found that biochemical reactions contributed by underground enzyme activities often enhance the in silico production of compounds with industrial importance, including several cases where underground activities are indispensable for production. Most of these new capabilities can be achieved by the addition of one or two underground reactions to the native network, suggesting that only a few side activities need to be enhanced during implementation. Remarkably, we find that the contribution of underground reactions to the production of value-added compounds is comparable to that of heterologous reactions, underscoring their biotechnological potential. Taken together, our genome-wide study demonstrates that exploiting underground enzyme activities could be a promising addition to the toolbox of industrial strain development.
The data and scripts underlying this article are available on GitHub at https://github.com/pappb/Kovacs-et-al-Underground-metabolism.
Supplementary data are available at Bioinformatics online.
增值化合物的生物生产通常通过利用来自其他物种的酶来实现。然而，由于宿主细胞内意外的相互作用，此类异源酶的表达可能是有害的。最近，出现了一种替代策略，该策略依赖于利用宿主酶的附带活性来建立新的生物合成途径。尽管这种低水平的“地下”酶活性很普遍，但它们是否可作为途径工程的重要资源仍未得到充分探索。
在这里，我们使用基因组规模建模来估计大肠杆菌中用于工程化新型生物合成途径的地下反应的理论潜力。我们发现，地下酶活性所促成的生化反应通常会提高具有工业重要性的化合物的计算机模拟产量，包括在几种情况下地下活性对于生产是不可或缺的。这些新能力中的大多数可以通过向天然网络添加一两个地下反应来实现，这表明在实施过程中只需增强少数附带活性。值得注意的是，我们发现地下反应对增值化合物生产的贡献与异源反应相当，突出了它们的生物技术潜力。综上所述，我们的全基因组研究表明，利用地下酶活性可能是工业菌株开发工具箱中一个有前途的补充。
本文所依据的数据和脚本可在GitHub上获取，网址为https://github.com/pappb/Kovacs-et-al-Underground-metabolism。
补充数据可在《生物信息学》在线版获取。
