ORIGINAL RESEARCH PAPER Metabolic engineering of Streptomyces venezuelae for malonyl-CoA biosynthesis to enhance heterologous production of polyketides Sushila Maharjan • Je Won Park • Yeo Joon Yoon • Hei Chan Lee • Jae Kyung Sohng Received: 15 September 2009 / Revised: 24 September 2009 / Accepted: 28 September 2009 / Published online: 17 October 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Using metabolic engineering, we devel- oped Streptomyces venezuelae YJ028 as an efficient heterologous host to increase the malonyl-CoA pool to be directed towards enhanced production of various polyketides. To probe the applicability of newly devel- oped hosts in the heterologous production of polyke- tides, we expressed type III polyketide synthase, 1,3,6,8-tetrahydroxynaphthalene synthase, in these hosts. Flaviolin production was doubled by expression of acetyl-CoA carboxylase (ACCase) and 4-fold by combined expression of ACCase, metK1-sp and afsR- sp. Thus, the newly developed Streptomyces venezu- elae YJ028 hosts produce heterologous polyketides more efficiently than the parent strain. Keywords Acetyl-CoA carboxylase Á Flaviolin Á Streptomyces venezuelae Á 1,3,6,8-tetrahydroxynaphthalene synthase Introduction Actinomycetes produce more than 10,000 drugs, many of which are polyketide-derived compounds. However, wild type strains are not optimal hosts for high-level polyketide production as they tend to grow slowly and their cellular metabolic networks are not optimized for industrial production. An approach to polyketide overproduction is the metabolic engineer- ing of a producer strain to develop a generic host into which polyketide synthase (PKS) genes and other essential genes could be readily transferred and functionally expressed (Olano et al. 2008). Alterna- tively, the polyketides can be produced in heterolo- gous hosts which can facilitate analysis of the catalytic properties of polyketide-producing enzymes and also offer an excellent opportunity for precursor- directed synthesis (Pfeifer and Khosla 2001). The usual heterologous host for polyketide pro- duction includes E. coli, Bacillus subtilis, Str. coeli- color, Saccharopolyspora erythraea, Str. lividans, and Str. fradiae. However, these heterologous hosts have slow growth rates and need relatively prolonged culture periods (6–9 days) to reach the maximum production level of metabolites. In contrast, Str. Electronic supplementary material The online version of this article (doi:10.1007/s10529-009-0152-9) contains supplementary material, which is available to authorized users. S. Maharjan Á H. C. Lee Á J. K. Sohng (&) Department of Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, 100, Kalsan-ri, Tangjeonmyun, Asansi, Chungnam 336-708, Republic of Korea e-mail: sohng@sunmoon.ac.kr J. W. Park Á Y. J. Yoon Division of Nano Sciences and Department of Chemistry, Ewha Womans University, 11-1, Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea 123 Biotechnol Lett (2010) 32:277–282 DOI 10.1007/s10529-009-0152-9