Industrial Metabolic Engineering

说明书(申请人提供)：本提案中描述的一种代谢工程，称为“工业”代谢工程，是一种利用体外转座诱变的能力在工业微生物中进行菌株改良的方法。对这项研究感兴趣的工业微生物是放线菌，这是一组土壤细菌，以其产生世界上三分之二以上的天然衍生抗生素、抗癌剂和目前用于医疗的免疫抑制剂的能力而闻名。工业代谢工程也受益于在微发酵筛选方面取得的技术进步。微发酵使大量突变体的经济筛选成为可能，以便找到改良的菌株。由于转座子标记过程，这些改进的突变体可以很容易地进行反向工程，以揭示它们基因组中包含的菌株改进突变的身份。一旦确定了菌株改良的目标，就会揭示新的遗传和代谢知识，从而进一步优化该技术，并将该技术推广到其他具有重要医学意义的工业发酵过程中。这项研究中使用的模式生物是红霉素产生生物红霉菌，它是50多年来密集的遗传和生化研究的主题，为工业微生物预测代谢工程这一新兴领域奠定了坚实的基础。1工业代谢工程代谢工程有朝一日将使科学家有能力为许多有用的目的预测性地操纵生物有机体，从菌种改良和其他工业生物技术应用，到允许更大的农业生产，允许更高效和更安全的能源生产，以及更好地了解有助于开发新疗法的医疗条件的代谢基础。对于一些有希望的新天然产品，我们的技术可以决定药物是进入市场，还是因用于测试或商业分销的药物供应不足而被放弃。

DESCRIPTION (provided by applicant): A type of metabolic engineering described in this proposal, and referred to as "industrial" metabolic engineering, is a method for performing strain improvement in industrial microorganisms by harnessing the power of in vitro transposition mutagenesis. The industrial microorganisms of interest to this study are the actinomycetes, a group of soil bacteria that are best known for their ability to produce over two thirds of the worlds naturally derived antibiotics, anticancer agents, and immunosuppressants currently in medical use. Industrial metabolic engineering also benefits from technical progress made in microfermentation screening. Microfermentations make possible the economical screening of large numbers of mutants in order find improved strains. Because of the transposon tagging process, these improved mutants can be easily reverse engineered to reveal the identity of the strain improvement mutation they harbor in their genome. Once the strain improvement target is identified, new genetic and metabolic knowledge is revealed that can lead to further optimization of the technology and extension of the technology to other industrial fermentation processes of medical importance. The model organism used in this study is the erythromycin producing organism, S. erythraea, that has been the subject of over 50 years of intensive genetic and biochemical research, providing a solid foundation upon which to build the fundamentals for the emerging field of predictive metabolic engineering of industrial microorganisms. 1 PROJECTNARRATIVE Industrial Metabolic Engineering Metabolic engineering will someday give scientists the ability to predicatively manipulate biological organisms for many useful purposes ranging from strain improvement and other industrial biotech applications, to allowing greater agricultural production, permitting more efficient and safer energy production, and providing better understanding of the metabolic basis for medical conditions that will assist in the development of new cures. For some promising new natural products, our technology could make the difference between a drug making it to market, or being abandoned due to inadequate supply of the drug for testing or commercial distribution.