Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands.
Biotechnol Adv. 2022 Nov;60:108035. doi: 10.1016/j.biotechadv.2022.108035. Epub 2022 Sep 9.
Metabolism has long been considered as a relatively stiff set of biochemical reactions. This somewhat outdated and dogmatic view has been challenged over the last years, as multiple studies exposed unprecedented plasticity of metabolism by exploring rational and evolutionary modifications within the metabolic network of cell factories. Of particular importance is the emergence of metabolic bypasses, which consist of enzymatic reaction(s) that support unnatural connections between metabolic nodes. Such novel topologies can be generated through the introduction of heterologous enzymes or by upregulating native enzymes (sometimes relying on promiscuous activities thereof). Altogether, the adoption of bypasses resulted in an expansion in the capacity of the host's metabolic network, which can be harnessed for bioproduction. In this review, we discuss modifications to the canonical architecture of central carbon metabolism derived from such bypasses towards six optimization purposes: stoichiometric gain, overcoming kinetic limitations, solving thermodynamic barriers, circumventing toxic intermediates, uncoupling product synthesis from biomass formation, and altering redox cofactor specificity. The metabolic costs associated with bypass-implementation are likewise discussed, including tailoring their design towards improving bioproduction.
长期以来，代谢被认为是一组相对僵硬的生化反应。这种有些过时和教条的观点在过去几年中受到了挑战，因为多项研究通过探索细胞工厂代谢网络中的合理和进化修饰，揭示了代谢前所未有的可塑性。特别重要的是代谢旁路的出现，它由支持代谢节点之间非自然连接的酶促反应组成。这种新颖的拓扑结构可以通过引入异源酶或上调天然酶（有时依赖于其混杂活性）来产生。总的来说，旁路的采用导致了宿主代谢网络容量的扩大，这可以用于生物生产。在这篇综述中，我们讨论了源自这些旁路的中心碳代谢的规范结构的修饰，以实现六个优化目的：化学计量增益、克服动力学限制、解决热力学障碍、绕过有毒中间体、将产物合成与生物量形成解耦，以及改变氧化还原辅因子特异性。还讨论了与旁路实施相关的代谢成本，包括针对改善生物生产来调整它们的设计。
