Synthetic Biology Tools for Novel Secondary Metabolite Discovery in Streptomyces

Lee, Namil; Hwang, Soonkyu; Lee, Yong Jae; Cho, Suhyung; Palsson, Bernhard Ø.; Cho, Byung-Kwan

doi:10.4014/jmb.1904.04015

Cited by 79 publications

(63 citation statements)

References 133 publications

(237 reference statements)

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“…Streptomyces, which comprise the largest genus of Actinobacteria, are huge natural reservoir of secondary metabolites, including antibiotics, immunosuppressants, and other medicinal compounds [1][2][3][4][5][6] . Recent advancements in high-throughput sequencing have led to the development of the genome mining approach, which implicates that the genome of each Streptomyces species has more than 30 secondary metabolite biosynthetic gene clusters (smBGCs) with potential to produce various unexplored secondary metabolites 2 .…”

Section: Background and Summarymentioning

confidence: 99%

Transcriptome and translatome profiles of Streptomyces species in different growth phases

et al. 2020

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Streptomyces are efficient producers of various bioactive compounds, which are mostly synthesized by their secondary metabolite biosynthetic gene clusters (smBGCs). The smBGCs are tightly controlled by complex regulatory systems at transcriptional and translational levels to effectively utilize precursors that are supplied by primary metabolism. Thus, dynamic changes in gene expression in response to cellular status at both the transcriptional and translational levels should be elucidated to directly reflect protein levels, rapid downstream responses, and cellular energy costs. In this study, RNA-Seq and ribosome profiling were performed for five industrially important Streptomyces species at different growth phases, for the deep sequencing of total mRNA, and only those mRNA fragments that are protected by translating ribosomes, respectively. Herein, 12.0 to 763.8 million raw reads were sufficiently obtained with high quality of more than 80% for the Phred score Q30 and high reproducibility. These data provide a comprehensive understanding of the transcriptional and translational landscape across the Streptomyces species and contribute to facilitating the rational engineering of secondary metabolite production.

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Section: Background and Summarymentioning

confidence: 99%

Transcriptome and translatome profiles of Streptomyces species in different growth phases

et al. 2020

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“…They play an important role for engineering of both, the natural producer and heterologous hosts. Challenges and new opportunities for the genetic manipulation of actinomycetes were recently reviewed [376][377][378][379][380][381].…”

Section: Strategies and Tools For The Discovery Of Natural Productsmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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“…Build tools are technical tools for preparing DNA parts, proteins, and hosts to test the experimental design from above. In recent decades synthetic biology tools have been rapidly developed, enabling large-scale, combinatorial, and highthroughput engineering (Winn et al, 2016;Lee et al, 2019). Despite these advanced tools, they are not frequently used for PKS and NRPS engineering as yet.…”

Section: Build Toolsmentioning

confidence: 99%

Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

Hwang

Lee

Cho

et al. 2020

Front. Mol. Biosci.

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In nature, various enzymes govern diverse biochemical reactions through their specific three-dimensional structures, which have been harnessed to produce many useful bioactive compounds including clinical agents and commodity chemicals. Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are particularly unique multifunctional enzymes that display modular organization. Individual modules incorporate their own specific substrates and collaborate to assemble complex polyketides or non-ribosomal polypeptides in a linear fashion. Due to the modular properties of PKSs and NRPSs, they have been attractive rational engineering targets for novel chemical production through the predictable modification of each moiety of the complex chemical through engineering of the cognate module. Thus, individual reactions of each module could be separated as a retro-biosynthetic biopart and repurposed to new biosynthetic pathways for the production of biofuels or commodity chemicals. Despite these potentials, repurposing attempts have often failed owing to impaired catalytic activity or the production of unintended products due to incompatible protein-protein interactions between the modules and structural perturbation of the enzyme. Recent advances in the structural, computational, and synthetic tools provide more opportunities for successful repurposing. In this review, we focused on the representative strategies and examples for the repurposing of modular PKSs and NRPSs, along with their advantages and current limitations. Thereafter, synthetic biology tools and perspectives were suggested for potential further advancement, including the rational and large-scale high-throughput approaches. Ultimately, the potential diverse reactions from modular PKSs and NRPSs would be leveraged to expand the reservoir of useful chemicals.

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Synthetic Biology Tools for Novel Secondary Metabolite Discovery in Streptomyces

Cited by 79 publications

References 133 publications

Transcriptome and translatome profiles of Streptomyces species in different growth phases

Transcriptome and translatome profiles of Streptomyces species in different growth phases

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

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