Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

Liu, Joyce F.; Zhu, Xuejun; Kim, Seong Jong; Zhang, Wenjun

doi:10.1039/c6np00004e

Cited by 71 publications

(77 citation statements)

References 129 publications

(492 reference statements)

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“…Antimycin-type compounds are a class of depsipeptides sharing a nine-membered bis -lactone ring with a conserved substitution of 3-formamidosalicylic acid, which exhibited a wide range of bioactivities including antifungal, insecticidal, antiviral, anticancer, and anti-inflammatory (Hosotani et al, 2005; Shiomi et al, 2005; Raveh et al, 2013; Liu J. et al, 2016). Antimycins are generated from a hybrid NRPS (non-ribosomal peptide synthetase)–PKS (polyketide synthase) assembly line in various Streptomyces species with the 3-formamidosalicylate substitution as a starter unit.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production

Huang

Hou

et al. 2017

Front. Microbiol.

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Deepsea microbes are a rich source of novel bioactive compounds, which have developed unique genetic systems as well as biosynthetic pathways compared with those of terrestrial microbes in order to survive in extreme living environment. However, a large variety of deepsea-microbial secondary metabolic pathways remain “cryptic” under the normal laboratory conditions. Manipulation of global regulators is one of the effective approaches for triggering the production of cryptic secondary metabolites. In this study, by combination of various chromatographic purification process, we obtained somalimycin (1), a new antimycin-type depsipeptide, with an unusual substitution of 3-aminosalicylate instead of conserved 3-formamidosalicylate moiety, along with two known (2 and 3) analogs from the ΔwblAso mutant strain of deepsea-derived Streptomyces somaliensis SCSIO ZH66. The structures of 1–3 were elucidated on the basis of extensive spectroscopic analyses including LC-MS and NMR. In the evaluation of potent anti-inflammatory activity, compound 2 exhibited strong inhibitory activity on the IL-5 production in ovalbumin-stimulated splenocytes with IC50 value of 0.57 μM, while 1 and 3 displayed mild effect (>10 μM), which might be attributed to their different side-chain substitutions. Moreover, compounds 1–3 showed very weak cytotoxicity against human umbilical vein endothelial cells with LD50 values of 62.6, 34.6, and 192.9 μM, respectively, which were far over their IL-5 inhibitory activity. These results indicated that these compounds have good potential for further use in anti-inflammatory drug development.

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Section: Discussionmentioning

confidence: 99%

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production

Huang

Hou

et al. 2017

Front. Microbiol.

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“…Antimycin-type depsipeptides are a family of natural products with various important biological activities such as anticancer, antifungal, and antiinflammatory activities (1). They share a 9-, 12-, 15-or 18-membered macrolide ring with an amide linkage to a conserved 3-formamidosalicylate (3-FAS) moiety.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Shen

Sun

Zhang

et al. 2020

Journal of Biological Chemistry

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Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

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“…Antimycin-type depsipeptides are a large class of natural products widely produced by Streptomyces species (see references 4 and 5 for recent reviews). Antimycins are the archetypal members of this family and have been known for more than 65 years (6).…”

Section: Introductionmentioning

confidence: 99%

Coordinate Regulation of Antimycin and Candicidin Biosynthesis

McLean

Hoskisson

Seipke

2016

mSphere

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Natural products produced by members of the phylum Actinobacteria underpin many industrially and medically important compounds; however, the majority of the ~30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. Understanding the diversity of regulatory strategies controlling the expression of these pathways is therefore critical if their biosynthetic potential is to be explored for new drug leads. Our findings reveal that the candicidin cluster-situated regulator FscRI coordinately controls the biosynthesis of both candicidin and antimycin, which is the first observation of cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products. We anticipate that this will emerge as a major strategy by which members of the phylum Actinobacteria coordinately produce natural products, which will advance our understanding of how the expression of secondary metabolism is controlled and will aid the pursuit of “silent” biosynthetic pathway activation.

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Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

Cited by 71 publications

References 129 publications

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production

Discovery of Antimycin-Type Depsipeptides from a wbl Gene Mutant Strain of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66 and Their Effects on Pro-inflammatory Cytokine Production

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Coordinate Regulation of Antimycin and Candicidin Biosynthesis

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