Collaborative Research: Metabolite damage - A stumbling block for synthetic biology

合成生物学使微生物、植物和动物细胞工程能够安装新的或重新设计的自然生物合成路线，以合成基于生物的产品，如新型生物燃料和药物。阻止合成生物学充分发挥其潜力的一个挑战是，需要控制不必要的化学或酶副反应造成的损害。如果不加以控制，这种损害可能会减少最终产品的产量，并毒化生产这些产品的细胞，即代谢物。因此，细胞必须要么修复受损的代谢物，要么将它们转化为无害的化合物。代谢物损伤及其控制类似于DNA和蛋白质的损伤和修复，但对其了解要少得多。该项目的目标是更好地了解哪些代谢物受到损害，细胞如何修复受损的代谢物，并开发预测代谢物损伤和修复的计算模型。该项目将通过为研究生和博士后研究员提供跨学科培训，促进下一代劳动力的发展。该项目还将为所有职业层次的生物学家开发一个化学信息学实践讲习班，其中将包括少数族裔服务机构的教员参与。化学(即非酶)或酶的副反应可以将代谢物转化为无用或有毒的化合物，这需要细胞有系统来处理这些损害产物。同样清楚的是，化学介导的代谢物损伤可以对细胞施加压力，以至于影响适应性，并可能干扰合成生物学的应用。研究表明，与迄今所知的为数不多的代谢产物损伤反应和损伤控制系统相比，存在的代谢物损伤反应和损伤控制系统要多得多。这个项目的目标是更好地了解哪些代谢物受到损害，以及细胞如何修复受损的代谢物。为了实现这一目标，这一合作项目将协调以下方面的进展：1)建立代谢物化学反应的公共数据库，使用算法预测此类反应，类似于KEGG/BioCyc对酶反应所做的工作；2)开发以理论为导向的方法，预测和验证损伤控制基因及其作用模式；3)开发代谢模型，预测损伤反应如何潜在地影响细胞生理学和合成生物学努力；以及4)在代谢组学图谱的数千个未知峰中识别损伤产物，这将允许基于计算算法验证预测的损伤代谢物。

Synthetic biology enables engineering of microbes, plants, and animal cells to install new or redesigned natural biosynthetic routes to synthesize biologically-based products such as novel biofuels and pharmaceuticals. One challenge preventing synthetic biology from reaching its full potential is the need to keep in check the damage caused by unwanted chemical or enzymatic side-reactions. When unchecked, this damage can diminish yields of end-products and poisons the cells making these products, referred to as metabolites. Consequently cells must either repair the damaged metabolite or convert them into harmless compounds. Metabolite damage and its control is analogous to DNA and protein damage and repair, but is much more poorly understood. The goal of this project is to develop a better understanding of which metabolites are damaged, how cells repair damaged metabolites, and to develop computational models for predicting metabolite damage and repair. This project will contribute to the development of the next generation work-force by providing cross-disciplinary training of graduate students and post-doctoral fellows. The project will also develop a hands-on workshop on chemoinformatics for biologists of all career levels that will include participation of faculty from minority-serving institutions. Chemical (i.e. non-enzymatic) or enzymatic side-reactions can convert metabolites to useless or toxic compounds, which requires cells to have systems to deal with these damage products. It is also clear that chemically-mediated metabolite damage can impose stress upon a cell to such an extent to influence fitness and possibly interfere with synthetic biology applications. Research suggests that there are far more metabolite damage reactions and damage-control systems than the few known so far. The goal of this project is to develop a better understanding of which metabolites are damaged and how cells repair damaged metabolites. To achieve this he goal this collaborative project will coordinate progress on: 1) building a public database of chemical reactions of metabolites with algorithms to predict such reactions analogous to what KEGG/BioCyc does for enzyme reactions; 2) development of a theory-driven approach to predict and validate damage-control genes and their mode of action; 3) developing metabolic models that predict how damage reactions potentially impact cellular physiology and synthetic biology efforts; and 4) identifying damage products among thousands of unknown peaks in metabolomics profiles, which will permit validation of predicted damaged metabolites based on computational algorithms.