Chapter 15
Biosynthesis of the Antifungal Polyketide Antibiotic Soraphen A in Sorangium cellulosum and Streptomyces lividans 1,2
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Downloaded by UNIV LAVAL on May 12, 2016 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0955.ch015
István Molnár , Ross Zirkle , and James M. Ligon
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Syngenta Biotechnology, Inc., Research Triangle Park, NC 27709 Current address: Southwest Center for Natural Product Research and Commercialization, University of Arizona, Tucson, A Z 85706 Current address: Martek Biosciences, 4909 Nautilus Court North, Boulder, C O 80301 Current address: BASF Agricultural Products, Research Triangle Park, NC 27709 4
The derivatization of soraphen by combinatorial biosynthesis has been a longstanding goal of the Natural Product Genetics group at Ciba Geigy - Novartis - Syngenta. We have cloned and characterized the soraphen A biosynthetic gene cluster of Sorangium cellulosum So ce26. To facilitate the genetic manipulation of So ce26, a central regulator of gliding motility was identified and its encoding gene disrupted to create a nonswarming strain. Despite this improvement, engineering of soraphen biosynthesis remained elusive in So ce26. Thus, the genes for the soraphen polyketide synthase, the postpolyketide tailoring steps, and methoxymalonate biosynthesis were introduced into Streptomyces lividans. Production of soraphen A in this genetically tractable strain also required provision of benzoyl-CoA by feeding benzoate or cinnamate.
© 2007 American Chemical Society
Rimando and Baerson; Polyketides ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
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Downloaded by UNIV LAVAL on May 12, 2016 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0955.ch015
218 The 18-membered macrolide polyketide soraphen A is produced by the myxobacterium Sorangium cellulosum So ce26 (/). Soraphen A shows a strong fungicidal activity against a wide range of species, notably against plant pathogenic fungi. It has a unique mode of action in inhibiting the biotin carboxylase domain of eukaryotic acetyl-coenzyme A carboxylases (ACCs) at nanomolar concentrations, thereby inhibiting fatty acid biosynthesis (2). Soraphen A was under development in the nineties at the Ciba Geigy - Novartis Agribusiness - Syngenta succession line of companies as an agricultural fungicide. In spite of an extensive chemical derivatization program, a weak but persistent teratogenic activity associated with all soraphen congeners and active semisynthetic derivatives eventually led to the discontinuation of development activities. Soraphen A , like several other previously "discarded" natural product leads [see the eventual success of daptomycin, (5)], however, might enjoy a revival not only as a "last line of defense" antifungal in immunocompromised patients with systemic fungal infections, but also in the unexpected fields of obesity and diabetes. Recent research suggests that malonyl-CoA, the product of A C C s , is a key metabolite in the regulation of energy homeostasis, with A C C 2 - (the mitochondrial isoform of ACCs) knockout mice maintaining low body weight with normal insulin- and blood glucose levels even on high fat / high carbohydrate diets (4, J). The availability of the crystal structure of soraphen A bound to the yeast A C C biotin carboxylase domain (
