Competition and co-regulation of spirotoamide and tautomycetin biosynthesis in Streptomyces griseochromogenes, and isolation and structural elucidation of spirotoamide C and D

Yang, Dong; Rateb, Mostafa E.; Wang, Nan; Shen, Ben

doi:10.1038/ja.2017.13

Cited by 4 publications

(8 citation statements)

References 20 publications

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“…According to the recently proposed design-build-test-learn cycle in metabolic engineering, global learning of cell metabolism and regulation facilitates efficient bioproduction (Chae et al, 2017;Hwang et al, 2014;Jarboe, 2018;Vavricka et al, 2020). Growing research indicates that multiple relationships exist between different secondary metabolite BGCs in one strain, such as coregulation, crossregulation, metabolic competition, and enzyme sharing (Chen et al, 2010;Kitani et al, 2009;Sun et al, 2002;Yang et al, 2017;X. C. Z. Zhang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The Streptomyces genome usually contains more than 20 secondary metabolite biosynthetic gene clusters (BGCs), including polyketide synthase (PKS), nonribosomal peptide synthetase (NRPS), terpenes and lanthipepteptides (Ikeda et al, 2003). Those secondary metabolite BGCs share complex metabolic and regulatory networks such as metabolic competition, transcriptional coregulation, cross‐regulation, and post‐modification enzyme sharing (Culp et al, 2019; Liu et al, 2013; Lu et al, 2016; Niu et al, 2016; Yang et al, 2017). Deleting PKS/PKS‐NRPS gene clusters improved intracellular concentrations of shared precursor malonyl‐CoA and methylmalonyl‐CoA (Lu et al, 2016), but deleting precursor shared BGCs does not always result in titer improvement and blocking the biosynthesis of nanchangmycin showed an insignificant effect on the production enhancement of meilingmycin in Streptomyces nanchangensis (Sun et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Yan et al, 2017;Yang et al, 2017). The pleiotropic effect of bottom-layer transcriptional activators on two or more secondary metabolites have been found in some Streptomyces and as an example, TntQ, a LuxR family regulator, activates both spirotoamide and tautomycetin production in Streptomyces griseochromogenes (Yang et al, 2017).…”

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confidence: 99%

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Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co‐activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis

Wang

Liu

et al. 2022

Biotech & Bioengineering

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Streptomyces bingchenggensis is a promising producer of milbemycins (MILs), the macrolide pesticide used widely in agriculture. The relationship between different biosynthetic gene clusters (BGCs) and the MIL BGC remains unclear, which hinders the precise metabolic engineering of S. bingchenggensis for titer improvement. To address this issue, this study discovered the regulatory function of a previously unidentified regulator KelR on a type‐II polyketide BGC, MIL BGC, and two other BGCs, and caused titer improvement. First, a type II polyketide synthase (PKS) gene cluster kel with a bidirectional effect on MIL biosynthesis was found using transcriptome analysis. A Streptomyces antibiotic regulatory protein (SARP) family regulator KelR from the kel cluster was then characterized as an activator of several BGCs including mil and kel clusters. Metabolic competition between mil and kel clusters at the late fermentation stage was confirmed. Finally, KelR and those BGCs were manipulated in S. bingchenggensis, which led to a 71.7% titer improvement of MIL A3/A4 to 4058.2 ± 71.0 mg/L. This study deciphered the regulatory function of a previously unidentified regulatory protein KelR on several BGCs including mil in S. bingchenggensis and provided an example of coordinating metabolic competition and coregulation for titer improvement of secondary metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co‐activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis

Wang

Liu

et al. 2022

Biotech & Bioengineering

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“…When more than one polyketide is encoded in the genome of the same strain, it is likely that one of these metabolites will be produced preferentially. Yang and colleagues () have recently reported that although spirotoamides and tautomycetin (TTN) are compounds synthesised by two distinct type I PKSs, competition for the same pool of acyl‐CoA precursors results in the preferential production of TTN in Streptomyces griseochromogenes . Deletion of the positive regulators involved in TTN biosynthesis liberates precursors for the production of spirotoamides.…”

Section: Physiological Regulation – Integrating Starvation Signals Inmentioning

confidence: 99%

Regulation of specialised metabolites in Actinobacteria – expanding the paradigms

Hoskisson

Fernández-Martínez

2018

Environ Microbiol Rep

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SummaryThe increase in availability of actinobacterial whole genome sequences has revealed huge numbers of specialised metabolite biosynthetic gene clusters, encoding a range of bioactive molecules such as antibiotics, antifungals, immunosuppressives and anticancer agents. Yet the majority of these clusters are not expressed under standard laboratory conditions in rich media. Emerging data from studies of specialised metabolite biosynthesis suggest that the diversity of regulatory mechanisms is greater than previously thought and these act at multiple levels, through a range of signals such as nutrient limitation, intercellular signalling and competition with other organisms. Understanding the regulation and environmental cues that lead to the production of these compounds allows us to identify the role that these compounds play in their natural habitat as well as provide tools to exploit this untapped source of specialised metabolites for therapeutic uses. Here, we provide an overview of novel regulatory mechanisms that act in physiological, global and cluster‐specific regulatory manners on biosynthetic pathways in Actinobacteria and consider these alongside their ecological and evolutionary implications.

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“…Recently, four new polyketides containing 6,6-spiroketal cores with two anomeric effects, and terminal amide were isolated. Spirotoamides A and B in 2012 by Nogawa et al 1 and the spirotoamides C and D in 2017 by Yang et al 2 All compounds were isolated from a fraction of the microbial metabolite of Streptomyces griseochromogenes JC82-1223, 3 presenting 9 or 10 stereogenic centers, in which the fragment containing the spiroketal contains 7 of them.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C

Rossini

Dias

2019

J. Braz. Chem. Soc.

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This work describes the preparation of the C(7)-C(20) fragment of spirotoamides A to C in a very elegant fashion, achievement very high levels of stereocontrol. The synthesis has been accomplished by a sequence involving 14 steps (0.36% overall yield, average of 81% for each step) in high diastereo and enantioselectivity, employing, as determining steps, asymmetric Mukaiyama and boron-mediated 1,5-anti promoted aldol reactions between α-methyl-β-hydroxyketones and aldehydes. Scheme 1. Retrosynthetic analysis. Scheme 2. Synthesis of aldehyde 10. Scheme 3. Synthesis of α-methyl-β-hydroxyketone 9. Scheme 4. Synthesis of α-methyl-β-hydroxyaldehyde 5. Scheme 5. Preparation of aldol adduct 19.Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C J. Braz. Chem. Soc. 1570 Scheme 6. Synthesis of acetonide 21 and indirect determination of the stereochemistry of diol 20. Scheme 7. Determination of the stereochemistry of the aldol adduct 19. Scheme 8. Determination of the relative stereochemistry of hydrofuran 23.

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Competition and co-regulation of spirotoamide and tautomycetin biosynthesis in Streptomyces griseochromogenes, and isolation and structural elucidation of spirotoamide C and D

Cited by 4 publications

References 20 publications

Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co‐activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis

Titer improvement of milbemycins via coordinating metabolic competition and transcriptional co‐activation controlled by Streptomyces antibiotic regulatory protein family regulator in Streptomyces bingchenggensis

Regulation of specialised metabolites in Actinobacteria – expanding the paradigms

Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C

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