Total synthesis and absolute configuration of avenolide, extracellular factor in Streptomyces avermitilis

Uchida, Miho; Takamatsu, Satoshi; Arima, Shiho; Miyamoto, Kiyoko T.; Kitani, Shigeru; Nihira, Takuya; Ikeda, Haruo; Nagamitsu, Tohru

doi:10.1038/ja.2011.90

Cited by 26 publications

(36 citation statements)

References 26 publications

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“…4) confirmed that the natural compound has the absolute configuration of 4S,10R. The 4S,10S isomer possessed half the activity of the 4S,10R isomer, whereas the 4R,10R-isomer and 10-deoxy form (21) showed much reduced activity, suggesting that the 4S-absolute configuration and the presence of a hydroxyl group at C-10 are important for the binding to or signal perception by AvaR1.…”

mentioning

confidence: 76%

Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis

Kitani

Miyamoto

Takamatsu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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149

145

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Gram-positive bacteria of the genus Streptomyces are industrially important microorganisms, producing >70% of commercially important antibiotics. The production of these compounds is often regulated by low-molecular-weight bacterial hormones called autoregulators. Although 60% of Streptomyces strains may use γ-butyrolactone–type molecules as autoregulators and some use furan-type molecules, little is known about the signaling molecules used to regulate antibiotic production in many other members of this genus. Here, we purified a signaling molecule (avenolide) from Streptomyces avermitilis —the producer of the important anthelmintic agent avermectin with annual world sales of $850 million—and determined its structure, including stereochemistry, by spectroscopic analysis and chemical synthesis as (4 S ,10 R )-10-hydroxy-10-methyl-9-oxo-dodec-2-en-1,4-olide, a class of Streptomyces autoregulator. Avenolide is essential for eliciting avermectin production and is effective at nanomolar concentrations with a minimum effective concentration of 4 nM. The aco gene of S. avermitilis, which encodes an acyl-CoA oxidase, is required for avenolide biosynthesis, and homologs are also present in Streptomyces fradiae , Streptomyces ghanaensis , and Streptomyces griseoauranticus , suggesting that butenolide-type autoregulators may represent a widespread and another class of Streptomyces autoregulator involved in regulating antibiotic production.

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mentioning

confidence: 76%

Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis

Kitani

Miyamoto

Takamatsu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

145

View full text Add to dashboard Cite

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“…A retro-synthetic strategy was pursued to allow for the production of avenolide from the convergent synthesis of three key fragments consisting of the iodide 11 , the aldehyde 12 and epoxy 10 (Figure 1C) following the reported protocol by Uchida et al 20 Starting from the commercially available 1-methyl-2-butene, a Sharpless asymmetric dihydroxylation 21 produced the diol intermediate 1 in 82% yield in a single step (Figure 1D). The desired key intermediates aldehyde 12 and iodo alkene 11 and epoxy 10 were also made following the same reported protocol except the use of TBDPS rather than TBS for improved reaction monitoring using TLC.…”

Section: Resultsmentioning

confidence: 99%

“…The experimental procedures were adopted from the publication by Uchida et.al. 20 with further optimizations and modifications that have been stated. Detailed experimental procedures for relevant intermediates are specified in materials and methods section of supplementary information.…”

Section: Methodsmentioning

confidence: 99%

Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones

Kapoor

Olivares

Nair

2020

Preprint

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small molecule microbial hormones drastically alter the expression profiles of 21 antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) 22 regulates production of avermectin, derivatives of which are used in the treatment of river 23 blindness and other parasitic diseases. Butenolides and γ-butyrolactones control 24 production of pharmaceutically important secondary metabolites by binding to TetR 25 family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy 26 for the production of avenolide. We present crystal structures of the butenolide receptor 27 AvaR1 in isolation, and in complex with avenolide, as well as AvaR1 bound to an 28 oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal 29 structures enable identification of 90 new actinobacteria that may be regulated by 30 butenolides, two of which are experimentally verified. These studies provide a foundation 31 for understanding regulation of microbial secondary metabolite production, which may be 32 exploited for the discovery and production of novel medicines. 33 34 35

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“…However, little is known about the biosynthetic pathways that elaborate butenolides, as opposed to canonical GBLs that can be produced enzymatically from commercially available precursors. To this end, we undertook a novel retro-synthetic strategy to afford the production of avenolide from the convergent synthesis of three key fragments consisting of the iodide 11, the aldehyde 12 and epoxy 10 ( Figure 1C) following the reported protocol by Uchida et al 20 Starting from the commercially available 1-methyl-2-butene, a Sharpless asymmetric dihydroxylation 21 produced the diol intermediate 1 in 82% yield in a single step ( Figure 1D). The desired key intermediates aldehyde 12 and iodo alkene 11 and epoxy 10 were also made following the same reported protocol except the use of TBDPS rather than TBS for improved reaction monitoring using TLC.…”

Section: Convergent Synthesis Of (4s 10r)-avenolide and Characterizamentioning

confidence: 99%

“…The experimental procedures were adopted from the publication by Uchida et.al. 20 This resulted in a simplified protocol for the synthesis of allyl alcohol 17 which otherwise was reported to be made in 2 additional reaction steps starting from epoxy 10 from. Acrylic group was added to ally alcohol 17 using DDQ by the reported procedure and followed by ring closing metathesis reaction to yield stereospecific (4S, 10R)-avenolide, 13.…”

Section: Total Synthesis Of Avenolidementioning

confidence: 99%

Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones

Kapoor

Olivares

Nair

2020

eLife

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Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates the production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic diseases. Butenolides and γ-butyrolactones control the production of pharmaceutically important secondary metabolites by binding to TetR family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy for the production of avenolide. We present crystal structures of the butenolide receptor AvaR1 in isolation and in complex with avenolide, as well as those of AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable the identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding the regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines.

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Total synthesis and absolute configuration of avenolide, extracellular factor in Streptomyces avermitilis

Cited by 26 publications

References 26 publications

Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis

Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis

Biochemical Basis for the Regulation of Biosynthesis of Antiparasitics by Bacterial Hormones

Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones

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