Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Biochemistry. 2011 Jun 21;50(24):5404-18. doi: 10.1021/bi200416g. Epub 2011 May 26.
Living organisms have evolved a vast array of catalytic functions that make them ideally suited for the production of medicinally and industrially relevant small-molecule targets. Indeed, native metabolic pathways in microbial hosts have long been exploited and optimized for the scalable production of both fine and commodity chemicals. Our increasing capacity for DNA sequencing and synthesis has revealed the molecular basis for the biosynthesis of a variety of complex and useful metabolites and allows the de novo construction of novel metabolic pathways for the production of new and exotic molecular targets in genetically tractable microbes. However, the development of commercially viable processes for these engineered pathways is currently limited by our ability to quickly identify or engineer enzymes with the correct reaction and substrate selectivity as well as the speed by which metabolic bottlenecks can be determined and corrected. Efforts to understand the relationship among sequence, structure, and function in the basic biochemical sciences can advance these goals for synthetic biology applications while also serving as an experimental platform for elucidating the in vivo specificity and function of enzymes and reconstituting complex biochemical traits for study in a living model organism. Furthermore, the continuing discovery of natural mechanisms for the regulation of metabolic pathways has revealed new principles for the design of high-flux pathways with minimized metabolic burden and has inspired the development of new tools and approaches to engineering synthetic pathways in microbial hosts for chemical production.
生物进化出了大量的催化功能，使它们非常适合生产具有医学和工业相关性的小分子靶标。事实上，微生物宿主中的天然代谢途径长期以来一直被用于大规模生产精细化学品和大宗商品化学品，并进行了优化。我们测序和合成 DNA 的能力不断提高，揭示了各种复杂而有用的代谢物生物合成的分子基础，并允许从头构建新型代谢途径，以在遗传上易于操作的微生物中生产新的和奇特的分子靶标。然而，这些工程化途径的商业可行工艺的发展目前受到我们识别或工程酶的能力的限制，这些酶具有正确的反应和底物选择性，以及确定和纠正代谢瓶颈的速度。在基础生物化学科学中理解序列、结构和功能之间关系的努力可以推进这些合成生物学应用的目标，同时也可以作为阐明酶体内特异性和功能以及重建复杂生化特征以供在活体模式生物中研究的实验平台。此外，对代谢途径调控的自然机制的不断发现，揭示了设计具有最小代谢负担的高通量途径的新原则，并激发了开发用于微生物宿主中化学生产的合成途径的新工具和方法。
