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Applied and Environmental Microbiology, April 2008, p. 1972-1979, Vol. 74, No. 7
0099-2240/08/$08.00+0     doi:10.1128/AEM.02296-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Enhanced Heterologous Production of Desosaminyl Macrolides and Their Hydroxylated Derivatives by Overexpression of the pikD Regulatory Gene in Streptomyces venezuelae{triangledown}

Won Seok Jung,1 Soon Jeong Jeong,2 Sung Ryeol Park,2 Cha Yong Choi,1 Byoung Chul Park,3 Je Won Park,2 and Yeo Joon Yoon2*

Interdisciplinary Program of Biochemical Engineering and Biotechnology, Seoul National University, San 56-1, Shilim-dong, Gwanak-gu, Seoul 151-742, South Korea,1 Division of Nano Sciences, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, South Korea,2 Proteome Research Lab, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon 305-600, South Korea3

Received 10 October 2007/ Accepted 22 January 2008

To elevate the production level of heterologous polyketide in Streptomyces venezuelae, an additional copy of the positive regulatory gene pikD was introduced into the pikromycin (Pik) polyketide synthase (PKS) deletion mutant of S. venezuelae ATCC 15439 expressing tylosin PKS genes. The resulting mutant strain showed enhanced production of both tylactone (TL) and desosaminyl tylactone (DesTL) of 2.7- and 17.1-fold, respectively. The notable increase in DesTL production strongly suggested that PikD upregulates the expression of the desosamine (des) biosynthetic gene cluster. In addition, two hydroxylated forms of DesTL were newly detected from the extract of this mutant. These hydroxylated forms presumably resulted from a PikD-dependent increase in expression of the pikC gene that encodes P450 hydroxylase. Gene expression analysis by reverse transcriptase PCR and bioconversion experiments of 10-deoxymethynolide, narbonolide, and TL into the corresponding desosaminyl macrolides indicated that PikD is a positive regulator of the des and pikC genes, as well as the Pik PKS genes. These results demonstrate the role of PikD as a pathway-specific positive regulator of the entire Pik biosynthetic pathway and its usefulness in the development of a host-vector system for efficient heterologous production of desosaminyl macrolides and novel hydroxylated compounds.

* Corresponding author. Mailing address: Division of Nano Sciences, Ewha Womans University, Seoul 120-750, South Korea. Phone: 82-2-3277-4082. Fax: 82-2-3277-3419. E-mail: joonyoon{at}ewha.ac.kr

{triangledown} Published ahead of print on 1 February 2008.

Applied and Environmental Microbiology, April 2008, p. 1972-1979, Vol. 74, No. 7
0099-2240/08/$08.00+0     doi:10.1128/AEM.02296-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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