Thakker Chandresh, Martínez Irene, Li Wei, San Ka-Yiu, Bennett George N
Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA.
J Ind Microbiol Biotechnol. 2015 Mar;42(3):403-22. doi: 10.1007/s10295-014-1560-y. Epub 2014 Dec 13.
The review describes efforts toward metabolic engineering of production of organic acids. One aspect of the strategy involves the generation of an appropriate amount and type of reduced cofactor needed for the designed pathway. The ability to capture reducing power in the proper form, NADH or NADPH for the biosynthetic reactions leading to the organic acid, requires specific attention in designing the host and also depends on the feedstock used and cell energetic requirements for efficient metabolism during production. Recent work on the formation and commercial uses of a number of small mono- and diacids is discussed with redox differences, major biosynthetic precursors and engineering strategies outlined. Specific attention is given to those acids that are used in balancing cell redox or providing reduction equivalents for the cell, such as formate, which can be used in conjunction with metabolic engineering of other products to improve yields. Since a number of widely studied acids derived from oxaloacetate as an important precursor, several of these acids are covered with the general strategies and particular components summarized, including succinate, fumarate and malate. Since malate and fumarate are less reduced than succinate, the availability of reduction equivalents and level of aerobiosis are important parameters in optimizing production of these compounds in various hosts. Several other more oxidized acids are also discussed as in some cases, they may be desired products or their formation is minimized to afford higher yields of more reduced products. The placement and connections among acids in the typical central metabolic network are presented along with the use of a number of specific non-native enzymes to enhance routes to high production, where available alternative pathways and strategies are discussed. While many organic acids are derived from a few precursors within central metabolism, each organic acid has its own special requirements for high production and best compatibility with host physiology.
这篇综述描述了有机酸生产的代谢工程方面的研究进展。该策略的一个方面涉及为设计的途径生成适量且合适类型的还原型辅因子。在设计宿主时，需要特别关注以适当形式（NADH或NADPH）捕获用于导致有机酸生物合成反应的还原力的能力，这还取决于所使用的原料以及生产过程中细胞高效代谢所需的能量需求。本文讨论了一些小分子一元酸和二元酸的形成及商业用途，并概述了氧化还原差异、主要生物合成前体和工程策略。特别关注那些用于平衡细胞氧化还原或为细胞提供还原当量的酸，例如甲酸盐，它可与其他产品的代谢工程结合使用以提高产量。由于许多广泛研究的酸都以草酰乙酸作为重要前体衍生而来，因此本文总结了这些酸中的几种的一般策略和特定成分，包括琥珀酸、富马酸和苹果酸。由于苹果酸和富马酸的还原程度低于琥珀酸，还原当量的可用性和需氧程度是优化这些化合物在各种宿主中生产的重要参数。还讨论了其他几种氧化程度更高的酸，因为在某些情况下，它们可能是所需产物，或者将其形成最小化以获得更高产量的还原程度更高的产物。文中介绍了典型中心代谢网络中各种酸之间的位置和连接关系，以及使用一些特定的非天然酶来增强高产途径的情况，同时还讨论了可用的替代途径和策略。虽然许多有机酸都源自中心代谢中的少数前体，但每种有机酸在高产以及与宿主生理的最佳兼容性方面都有其特殊要求。
