ORIGINAL PAPER Rational design for over-production of desirable microbial metabolites by precision engineering Hong Gao • Xianlong Zhou • Zhongxuan Gou • Ying Zhuo • Chengzhang Fu • Mei Liu • Fuhang Song • Elizabeth Ashforth • Lixin Zhang Received: 6 December 2009 / Accepted: 1 April 2010 Ó Springer Science+Business Media B.V. 2010 Abstract Microbes represent a valuable source of commercially significant natural products that have improved our quality of life. Precision engineering can be used to precisely identify and specifically modify genes responsible for production of natural products and improve this production or modify the genes creating products that would not otherwise be produced. There have been several success stories concerning the manipulation of regulatory genes, pathways, and genomes to increase the productivity of industrial microbes. This review will focus on the strategies and integrated approaches for precisely deciphering regulatory genes by various modern techniques. The applications of precision engineering in rational strain improvement also shed light on the biology of natural microbial systems. Keywords Precision engineering Á Regulatory gene Á Strain improvement Abbreviations pre-NDA pre-New drug application MFA Metabolic flux analysis SAM S-adenosylmethionine CoA Coenzyme A 1,3-PD 1,3-Propanediol ALDH Aldehyde dehydrogenase DCA Dicarboxylic acid TCA Tricarboxylic acid HMG-CoA 3-hydroxy-3-methyl-glutaryl- coenzyme A ADS Amorphadiene synthase tHMGR HMG-CoA reductase CEF control effective flux PCA Principal component analysis Introduction Microbes are used in biotechnology industries to produce a wide variety of diverse compounds, which are important in chemical, food, pharmaceutical and health care fields (Davies 2009; Newman and Cragg 2007). In many cases, production of compounds directly by microbial fermentation is much more economical than using synthetic chemistry, e.g., steroids, beta-lactams, and erythromycin. Indeed, the potential to commercialize a compound without chemical modification distinguishes natural products H. Gao, X. Zhou, and Z. Gou contributed equally to this work. H. Gao Á X. Zhou Á Z. Gou Á Y. Zhuo Á C. Fu Á M. Liu Á F. Song Á E. Ashforth Á L. Zhang (&) Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People’s Republic of China e-mail: lzhang03@gmail.com Y. Zhuo Á C. Fu Graduate University of Chinese Academy of Sciences, Beijing, People’s Republic of China 123 Antonie van Leeuwenhoek DOI 10.1007/s10482-010-9442-4