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Applied and Environmental Microbiology, August 2005, p. 4862-4871, Vol. 71, No. 8
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.8.4862-4871.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Insights into the Biosynthesis of the Benzoquinone Ansamycins Geldanamycin and Herbimycin, Obtained by Gene Sequencing and Disruption

Andreas Rascher,^* Zhihao Hu, Greg O. Buchanan, Ralph Reid, and C. Richard Hutchinson

Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545

Received 21 December 2004/ Accepted 14 March 2005

Geldanamycin and the closely related herbimycins A, B, and C were the first benzoquinone ansamycins to be extensively studied for their antitumor properties as small-molecule inhibitors of the Hsp90 protein chaperone complex. These compounds are produced by two different Streptomyces hygroscopicus strains and have the same modular polyketide synthase (PKS)-derived carbon skeleton but different substitution patterns at C-11, C-15, and C-17. To set the stage for structural modification by genetic engineering, we previously identified the gene cluster responsible for geldanamycin biosynthesis. We have now cloned and sequenced a 115-kb segment of the herbimycin biosynthetic gene cluster from S. hygroscopicus AM 3672, including the genes for the PKS and most of the post-PKS tailoring enzymes. The similarities and differences between the gene clusters and biosynthetic pathways for these closely related ansamycins are interpreted with support from the results of gene inactivation experiments. In addition, the organization and functions of genes involved in the biosynthesis of the 3-amino-5-hydroxybenzoic acid (AHBA) starter unit and the post-PKS modifications of progeldanamycin were assessed by inactivating the subclusters of AHBA biosynthetic genes and two oxygenase genes (gdmM and gdmL) that were proposed to be involved in formation of the geldanamycin benzoquinoid system. A resulting novel geldanamycin analog, KOS-1806, was isolated and characterized.

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* Corresponding author. Mailing address: Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545. Phone: 01149-8131-666348. Fax: 01149-8131-54999. E-mail: andreas.rascher{at}gmail.com.

Supplemental material for this article may be found at http://aem.asm.org/.

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Applied and Environmental Microbiology, August 2005, p. 4862-4871, Vol. 71, No. 8
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.8.4862-4871.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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