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J. Microbiol. Biotechnol. 2008; 18(6): 1101-1108

Published online June 28, 2008

Copyright © The Korean Society for Microbiology and Biotechnology.

Characterization of Tailoring Genes Involved in the Modification of Geldanamycin Polyketide in Streptomyces hygroscopicus JCM4427

Shin, Jin-Chul , Zhu Na , Dong-Ho Lee 1, Won-Cheol Kim 1, Kyeong Lee 1, Yue-Mao Shen 2, Sang-Gi Paik 3, Young-Soo Hong 3* and Jung-Joon Lee 3*

Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea, 1Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-705, Korea, 2State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China, 3Chungnam National University, Daejeon 305-764, Korea

Abstract

Geldanamycin and its analogs are important anticancer agents that inhibit the newly targeted heat-shock protein (Hsp) 90, which is a chaperone protein in eukaryotic cells. To resolve which geldanamycin biosynthetic genes are responsible for particular post-polyketide synthase (PKS) processing steps and in which order the reactions occur, we individually inactivated candidate genes in Streptomyces hygroscopicus subsp. duamyceticus JCM4427 and isolated and elucidated the structures of intermediates from each mutant. The results indicated that gel7 governs at least one of the benzoquinone ring oxidation steps. The gel16 was found to be involved in double-bond formation between C-4 and C-5 of 4,5-dihydrogeldanamycin, which confirmed our previous findings that this double bond is reduced during the post-PKS modification of the polyketide assembly. In addition, pro-geldanamycin, which does not possess a double bond at C-4/5, was purified from the gel7 and gel8 double-gene-inactivated mutant.

Keywords: Geldanamycin, biosynthesis, Streptomyces, Streptomyces