de Moura Ferreira Maurício Alexander, de Almeida Eduardo Luís Menezes, da Silveira Wendel Batista, Nikoloski Zoran
Department of Microbiology, Federal University of Viçosa, Viçosa, Minas Gerais 36570900, Brazil.
Bioinformatics, Institute of Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Germany.
iScience. 2025 Feb 28;28(3):112126. doi: 10.1016/j.isci.2025.112126. eCollection 2025 Mar 21.
Integrating enzyme parameters into constraint-based models have significantly improved the prediction of physiological and molecular traits. To further improve these models, we integrated promiscuous enzyme activities that jointly comprise the so-called underground metabolism by developing the CORAL toolbox, which increases the resolution of modeled enzyme resource allocation. Applying CORAL to a protein-constrained model of revealed that underground metabolism resulted in larger flexibility of metabolic fluxes and enzyme usage. Simulating metabolic defects where the main activity of a promiscuous enzyme was blocked but promiscuous activities remained functional showed a small enzyme redistribution to the side activities. Further, blocking pairs of main activities showed that non-promiscuous enzymes exhibited larger impact on growth than promiscuous enzymes. These simulations showed that promiscuous enzymes can compensate for these defects, in line with experimental evidence. Together, our results indicated that promiscuous enzyme activities are vital to maintain robust metabolic function and growth.
将酶参数整合到基于约束的模型中显著改善了对生理和分子特征的预测。为了进一步改进这些模型，我们通过开发CORAL工具箱整合了混杂酶活性，这些活性共同构成了所谓的地下代谢，从而提高了建模酶资源分配的分辨率。将CORAL应用于一个蛋白质受限模型表明，地下代谢导致代谢通量和酶使用具有更大的灵活性。模拟混杂酶的主要活性被阻断但混杂活性仍起作用的代谢缺陷，结果显示酶会少量重新分配到次要活性。此外，阻断主要活性对显示非混杂酶对生长的影响大于混杂酶。这些模拟表明，混杂酶可以弥补这些缺陷，这与实验证据一致。总之，我们的结果表明，混杂酶活性对于维持强大的代谢功能和生长至关重要。
