From Microbial Differentiation to Ribosome Engineering

Ochi, Kozo

doi:10.1271/bbb.70007

Cited by 137 publications

(113 citation statements)

References 83 publications

(97 reference statements)

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“…11,21 We showed that scandium and lanthanum are both effective not only for enhancement of actinorhodin production but also for activation of silent or poorly expressed genes in S. coelicolor. In particular, scandium appears to be a feasible reagent for gene activation because it showed a rather wide range of effective concentrations.…”

Section: Resultsmentioning

confidence: 96%

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Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

2010

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Genome sequencing projects have revealed many biosynthesis gene clusters for the production of as-yet unknown secondary metabolites, especially in actinomycetes. Here, we report that the rare earth elements, scandium and/or lanthanum, markedly activate, ranging from 2.5-to 12-fold, the expression of nine genes belonging to nine secondary metabolite-biosynthetic gene clusters of Streptomyces coelicolor A3(2) when added to the medium at low concentrations. HPLC analysis of ethyl acetateextractable metabolites indicated the detectability of several compounds only in the rare earth-treated cultures. This approach should facilitate discovery of new biologically active compounds and the study of secondary metabolite production.

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Section: Resultsmentioning

confidence: 96%

“…6 Our laboratory has previously developed a method to increase antibacterial production. [7][8][9] This new approach, called 'ribosome engineering' , 10,11 has several advantages. In this method, bacteria are grown on antibiotics to select antibioticresistant strains.…”

Section: Introductionmentioning

confidence: 99%

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

2010

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“…They mapped the mutation to a ribosomal protein and showed that only the mutant ribosome led to activation of the silent Act gene cluster (act), thus demonstrating translational control in Act biosynthesis. The method has been extended to other antibiotics and many successful applications have followed (Ochi 2007;Ochi and Hosaka 2013). Ochi and Hosaka (2013) have recently provided a comprehensive summary of the applications of ribosome engineering.…”

Section: Motivationmentioning

confidence: 99%

Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules

Okada¹,

Seyedsayamdost²

2016

FEMS Microbiology Reviews

181

150

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One sentence summary: Microbial secondary metabolites represent a significant source of potential drug leads; however, the majority of the corresponding biosynthetic genes are not expressed under normal laboratory conditions. In this review, we assess the capacity of exogenous small molecules, especially antibiotics, to activate these silent gene clusters. Editor: Aimee Shen ABSTRACTNatural products have traditionally served as a dominant source of therapeutic agents. They are produced by dedicated biosynthetic gene clusters that assemble complex, bioactive molecules from simple precursors. Recent genome sequencing efforts coupled with advances in bioinformatics indicate that the majority of biosynthetic gene clusters are not expressed under normal laboratory conditions. Termed 'silent' or 'cryptic', these gene clusters represent a treasure trove for discovery of novel small molecules, their regulatory circuits and their biosynthetic pathways. In this review, we assess the capacity of exogenous small molecules in activating silent secondary metabolite gene clusters. Several approaches that have been developed are presented, including coculture techniques, ribosome engineering, chromatin remodeling and high-throughput elicitor screens. The rationale, applications and mechanisms attendant to each are discussed. Some general conclusions can be drawn from our analysis: exogenous small molecules comprise a productive avenue for the discovery of cryptic metabolites. Specifically, growth-inhibitory molecules, in some cases clinically used antibiotics, serve as effective inducers of silent biosynthetic gene clusters, suggesting that old antibiotics may be used to find new ones. The involvement of natural antibiotics in modulating secondary metabolism at subinhibitory concentrations suggests that they represent part of the microbial vocabulary through which inter-and intraspecies interactions are mediated.

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“…Importantly, despite the wide or ubiquitous distribution of relA or RSH in bacteria and plants, neither relA and RSH genes nor ppGpp per se have yet been identified in animals or eukaryotic micro-organisms such as yeasts and fungi. Although the mechanism of ppGpp synthesis is rather poorly understood Tozawa & Nomura, 2011;Tozawa et al, 2007), there is accumulating evidence regarding the function of ppGpp in reorienting cellular metabolism and its physiological consequences, including research into sporulation (Balzer & McLean, 2002;Lemos et al, 2004;Ochi et al, 1981), competence (Inaoka & Ochi, 2002), fruiting body formation (Harris et al, 1998), antibiotic production (Bibb, 2005;Hesketh et al, 2001;Hoyt & Jones, 1999;Inaoka et al, 2003;Ochi, 1987aOchi, , 2007Sun et al, 2001), development of persistence (Dahl et al, 2003;Korch et al, 2003), quorum sensing (Baysse et al, 2005;Harris et al, 1998;van Delden et al, 2001), biofilm formation (Balzer & McLean, 2002), pathogenesis (Erickson et al, 2004;Gaynor et al, 2005;Godfrey et al, 2002;Haralalka et al, 2003;Pizarro-Cerdá & Tedin, 2004;Song et al, 2004) and symbiosis (Moris et al, 2005;Wells & Long, 2002;Zhang et al, 2004). The RNA polymerase is the primary target for ppGpp, as confirmed recently by X-ray crystallographic analysis of an RNA polymerase-ppGpp complex (Artsimovitch et al, 2004;Chatterji et al, 1998;Sato et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Heterologous expression of a plant RelA-SpoT homologue results in increased stress tolerance in Saccharomyces cerevisiae by accumulation of the bacterial alarmone ppGpp

et al. 2012

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The bacterial alarmone ppGpp is present only in bacteria and the chloroplasts of plants, but not in mammalian cells or eukaryotic micro-organisms such as yeasts and fungi. The importance of the ppGpp signalling system in eukaryotes has therefore been largely overlooked. Here, we demonstrated that heterologous expression of a relA-spoT homologue (Sj-RSH) isolated from the halophilic plant Suaeda japonica in the yeast Saccharomyces cerevisiae results in accumulation of ppGpp, accompanied by enhancement of tolerance against various stress stimuli, such as osmotic stress, ethanol, hydrogen peroxide, high temperature and freezing. Unlike bacterial ppGpp accumulation, ppGpp was accumulated in the early growth phase but not in the late growth phase. Moreover, nutritional downshift resulted in a decrease in ppGpp level, suggesting that the observed Sj-RSH activity to synthesize ppGpp is not starvation-dependent, contrary to our expectations based on bacteria. Accumulated ppGpp was found to be present solely in the cytosolic fraction and not in the mitochondrial fraction, perhaps reflecting the ribosomeindependent ppGpp synthesis in S. cerevisiae cells. Unlike bacterial inosine monophosphate (IMP) dehydrogenases, the IMP dehydrogenase of S. cerevisiae was insensitive to ppGpp. Microarray analysis showed that ppGpp accumulation gave rise to marked changes in gene expression, with both upregulation and downregulation, including changes in mitochondrial gene expression. The most prominent upregulation (38-fold) was detected in the hypothetical gene YBR072C-A of unknown function, followed by many other known stress-responsive genes. S. cerevisiae may provide new opportunities to uncover and analyse the ppGpp signalling system in eukaryotic cells.

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From Microbial Differentiation to Ribosome Engineering

Cited by 137 publications

References 83 publications

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules

Heterologous expression of a plant RelA-SpoT homologue results in increased stress tolerance in Saccharomyces cerevisiae by accumulation of the bacterial alarmone ppGpp

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