Department of Microbiology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil.
Bioinformatics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany.
PLoS Comput Biol. 2023 Oct 19;19(10):e1011549. doi: 10.1371/journal.pcbi.1011549. eCollection 2023 Oct.
Protein allocation determines the activity of cellular pathways and affects growth across all organisms. Therefore, different experimental and machine learning approaches have been developed to quantify and predict protein abundance and how they are allocated to different cellular functions, respectively. Yet, despite advances in protein quantification, it remains challenging to predict condition-specific allocation of enzymes in metabolic networks. Here, using protein-constrained metabolic models, we propose a family of constrained-based approaches, termed PARROT, to predict how much of each enzyme is used based on the principle of minimizing the difference between a reference and an alternative growth condition. To this end, PARROT variants model the minimization of enzyme reallocation using four different (combinations of) distance functions. We demonstrate that the PARROT variant that minimizes the Manhattan distance between the enzyme allocation of a reference and an alternative condition outperforms existing approaches based on the parsimonious distribution of fluxes or enzymes for both Escherichia coli and Saccharomyces cerevisiae. Further, we show that the combined minimization of flux and enzyme allocation adjustment leads to inconsistent predictions. Together, our findings indicate that minimization of protein allocation rather than flux redistribution is a governing principle determining steady-state pathway activity for microorganism grown in alternative growth conditions.
蛋白质分配决定了细胞途径的活性，并影响所有生物体的生长。因此，已经开发了不同的实验和机器学习方法来量化和预测蛋白质丰度，以及它们分别如何分配到不同的细胞功能中。然而，尽管在蛋白质定量方面取得了进展，但预测代谢网络中酶的特定条件分配仍然具有挑战性。在这里，我们使用蛋白质约束代谢模型，提出了一系列称为 PARROT 的基于约束的方法，以根据最小化参考和替代生长条件之间差异的原则来预测每种酶的使用量。为此，PARROT 变体使用四种不同的（组合）距离函数来模拟酶再分配的最小化。我们证明，在大肠杆菌和酿酒酵母中，最小化参考和替代条件下酶分配之间曼哈顿距离的 PARROT 变体优于基于通量或酶简约分布的现有方法。此外，我们表明通量和酶分配调整的综合最小化导致不一致的预测。总之，我们的研究结果表明，蛋白质分配的最小化而不是通量再分配是决定在替代生长条件下生长的微生物中稳态途径活性的主要原则。
