Depatment of Chemical Engineering, University of Delaware & the Delaware Biotechnology Institute, Newark, DE 19711, USA.
Metab Eng. 2010 Jul;12(4):307-31. doi: 10.1016/j.ymben.2010.03.004. Epub 2010 Mar 24.
Metabolites, substrates and substrate impurities may be toxic to cells by damaging biological molecules, organelles, membranes or disrupting biological processes. Chemical stress is routinely encountered in bioprocessing to produce chemicals or fuels from renewable substrates, in whole-cell biocatalysis and bioremediation. Cells respond, adapt and may develop tolerance to chemicals by mechanisms only partially explored, especially for multiple simultaneous stresses. More is known about how cells respond to chemicals, but less about how to develop tolerant strains. Aiming to stimulate new metabolic engineering and synthetic-biology approaches for tolerant-strain development, this review takes a holistic, comparative and modular approach in bringing together the large literature on genes, programs, mechanisms, processes and molecules involved in chemical stress or imparting tolerance. These include stress proteins and transcription factors, efflux pumps, altered membrane composition, stress-adapted energy metabolism, chemical detoxification, and accumulation of small-molecule chaperons and compatible solutes. The modular organization (by chemicals, mechanism, organism, and methods used) imparts flexibility in exploring this complex literature, while comparative analyses point to hidden commonalities, such as an oxidative stress response underlying some solvent and carboxylic-acid stress. Successes involving one or a few genes, as well as global genomic approaches are reviewed with an eye to future developments that would engage novel genomic and systems-biology tools to create altered or semi-synthetic strains with superior tolerance characteristics for bioprocessing.
代谢物、底物和底物杂质可能通过破坏生物分子、细胞器、膜或扰乱生物过程对细胞产生毒性。在利用可再生底物生产化学品或燃料、全细胞生物催化和生物修复的生物加工中，经常会遇到化学应激。细胞通过部分探索的机制来应对、适应和可能发展出对化学品的耐受性，特别是对于多种同时存在的应激。人们对细胞如何应对化学品有了更多的了解，但对如何开发耐受菌株了解较少。本综述采用整体、比较和模块化的方法，汇集了大量关于参与化学应激或赋予耐受性的基因、程序、机制、过程和分子的文献，旨在为耐受菌株的开发激发新的代谢工程和合成生物学方法。这些包括应激蛋白和转录因子、外排泵、改变的膜组成、应激适应的能量代谢、化学解毒以及小分子伴侣和相容溶质的积累。模块化组织（按化学物质、机制、生物体和使用的方法）赋予了灵活探索这一复杂文献的能力，而比较分析指出了隐藏的共性，例如一些溶剂和羧酸应激的基础是氧化应激反应。本文回顾了涉及一个或几个基因的成功案例，以及全基因组方法，以期未来能够利用新的基因组和系统生物学工具来创建具有卓越耐受特性的改变或半合成菌株，用于生物加工。
