Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 50, Pages 34557-34568Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.602334
Keywords
Actinobacteria; Bacterial Genetics; Gene Knockout; Natural Product Biosynthesis; Polyketide; Streptomyces galbus; Galbonolide; Highly Reducing Type I Polyketide Synthase
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Funding
- National Research Foundation of Korea (NRF) by the Ministry of Education [2011-0021169, 2013R1A1A2059458]
- Rural Development Administration, Republic of Korea [PJ009643]
- National Research Foundation of Korea [2013R1A1A2059458, 2011-0021169] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Background: Galbonolide (GAL) was proposed to be synthesized by a modular type I polyketide synthase (PKS) with GalA-E serving a supporting role. Results: GalA-C constitute a sole type I PKS that is involved in GAL biosynthesis in S. galbus. Conclusion: GalA-C catalyze the de novo formation of GAL macrolactone. Significance: GalA-C constitute a novel iterative PKS that incorporates methylmalonate units with highly programmed -keto group modifications. Galbonolide (GAL) A and B are antifungal macrolactone polyketides produced by Streptomyces galbus. During their polyketide chain assembly, GAL-A and -B incorporate methoxymalonate and methylmalonate, respectively, in the fourth chain extension step. The methoxymalonyl-acyl carrier protein biosynthesis locus (galG to K) is specifically involved in GAL-A biosynthesis, and this locus is neighbored by a gene cluster composed of galA-E. GalA-C constitute a single module, highly reducing type I polyketide synthase (PKS). GalD and GalE are cytochrome P450 and Rieske domain protein, respectively. Gene knock-out experiments verified that galB, -C, and -D are essential for GAL biosynthesis. A galD mutant accumulated a GAL-C that lacked two hydroxyl groups and a double bond when compared with GAL-B. A [U-C-13]propionate feeding experiment indicated that no rare precursor other than methoxymalonate was incorporated during GAL biogenesis. A search of the S. galbus genome for a modular type I PKS system, the type that was expected to direct GAL biosynthesis, resulted in the identification of only one modular type I PKS gene cluster. Homology analysis indicated that this PKS gene cluster is the locus for vicenistatin biosynthesis. This cluster was previously reported in Streptomyces halstedii. A gene deletion of the vinP2 ortholog clearly demonstrated that this modular type I PKS system is not involved in GAL biosynthesis. Therefore, we propose that GalA-C direct macrolactone polyketide formation for GAL. Our studies provide a glimpse into a novel biochemical strategy used for polyketide synthesis; that is, the iterative assembly of propionates with highly programmed -keto group modifications.
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