In this study, we first establish heterologous expression systems of the unique antimycin-type cyclic depsipeptides: JBIR tri-lactone and neoantimycin tetra-lactone , and engineer their biosyntheses by taking advantage of bioinformatic analyses and evolutionary insights. As a result, we successfully accomplish three manipulations: i ring contraction of neoantimycin from tetra-lactone to tri-lactone , ii ring expansion of JBIR from tri-lactone to tetra-lactone , and iii alkyl chain diversification of JBIR by the incorporation of various alkylmalonyl-CoA extender units, to generate a set of unnatural derivatives in practical yields. Polyketides and non-ribosomal peptide hybrids are an important class of natural products, and include a variety of bioactive compounds, exemplified by the anti-cancer agents, bleomycin, epothilone, and calyculin 1 — 4. They are built up by a complex system composed of polyketide synthases PKSs and non-ribosomal peptide synthetases NRPSs 5 — 7 , which are thiotemplate module enzymes consisting of several catalytic domains. In the PKS system, the ketosynthase KS domain catalyzes decarboxylative Claisen condensation between a starter acyl group and an extender unit thioesterified to an acyl carrier protein ACP via the action of an acyltransferase AT , during a single polyketide extension cycle. In the NRPS system, the amino acid building blocks are activated as adenylates and thioesterified to the thiolation T domain by the adenylation A domain.
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These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.
Find more information on the Altmetric Attention Score and how the score is calculated. The first total syntheses of JBIR and two analogous depsipeptides, membered antimycin-class antibiotics, have been accomplished via Shiina macrolactonization.
Comparison of the spectroscopic data of the synthesized compounds with those reported for natural products verified that the absolute configutation of the natural products was 2 S ,4 S ,6 S ,7 R ,14 S. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society.
For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. More by Chie Hamada. More by Yoshinosuke Usuki. More by Daiki Takeuchi. More by Hikaru Ogawa. More by Ryota Abe. More by Tetsuya Satoh. Cite this: Org. Article Views Altmetric -. Citations 1. Supporting Information. Cited By. This article is cited by 1 publications. On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone—proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino depsipeptide mimics.
Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution
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The regulation and biosynthesis of antimycins
This article is part of the Thematic Series "Natural products in synthesis and biosynthesis". Guest Editor: J. Dickschat Beilstein J. Antimycin A is widely used as a piscicide in the catfish farming industry and also has potent killing activity against insects, nematodes and fungi. The mode of action of antimycins is to inhibit cytochrome c reductase in the electron transport chain and halt respiration. However, more recently, antimycin A has attracted attention as a potent and selective inhibitor of the mitochondrial anti-apoptotic proteins Bcl-2 and Bcl-x L.
Chemical and Biosynthetic Evolution of the Antimycin-Type Depsipeptides
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