Structural Diversification of Lyngbyatoxin A by Host‐Dependent Heterologous Expression of the <i>tleABC</i> Biosynthetic Gene Cluster

Zhang, Lihan; Hoshino, Shotaro; Awakawa, Takayoshi; Wakimoto, Toshiyuki; Abe, Ikuro

doi:10.1002/cbic.201600229

Cited by 13 publications

(10 citation statements)

References 32 publications

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“…The limited host range of genetic elements like conjugal plasmids or pathogenicity islands as well as codon usage, the availability of metabolic precursors, or differences in transcription and regulation place restrictions on horizontal gene cluster transfer making the spread of natural product biosynthetic pathways more common among closely related organisms . However, horizontal gene transfers are necessary to explain the production of identical secondary metabolites by microbes belonging to different phyla, for example, the lyngbyatoxin biosynthetic pathway is found in both the actinobacteria and cyanobacteria phyla , while the macrolide scytophycin is found in both the proteobacteria and cyanobacteria phyla . The same natural product can also be shared between organisms from different domains, for example, the UV‐sunscreen mycosporine is produced by a range of photosynthetic algae and bacteria , the beta‐lactam antibiotic penicillins and cephalosporins are produced by fungi and bacteria , and potent neurotoxic saxitoxins are produced by both cyanobacteria and dinoflagellates.…”

Section: Horizontal Gene Transfer Facilitates the Distribution Of Natmentioning

confidence: 99%

A pharmaceutical model for the molecular evolution of microbial natural products

Fewer

Metsä‐Ketelä

2019

The FEBS Journal

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Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two‐step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre‐existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.

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Section: Horizontal Gene Transfer Facilitates the Distribution Of Natmentioning

confidence: 99%

A pharmaceutical model for the molecular evolution of microbial natural products

Fewer

Metsä‐Ketelä

2019

The FEBS Journal

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“…Expression of tleABC in three different hosts S. albus G153, S. lividans TK21 and S. avermitilis SUKA22 revealed unexpected host-pathway interactions. Although two intermediates valindolmycin and indolactam V and the final product lyngbyatoxin A were detected in all hosts, new analogues that are absent in both native producer and hosts were produced (Zhang et al, 2016a). Interestingly, these analogues were produced in a host-specific manner; different host preferably recognizes different compounds in the lyngbyatoxin pathway.…”

Section: Streptomyces Lividans As a Heterologous Hostmentioning

confidence: 99%

“…For example, S. lividans used indolactam V to generate analogues; while S. albus and S. avermitilis interacted with the early intermediate valindolmycin and the final product lyngbyatoxin A, respectively. The host specific generation of lyngbyatoxin A analogues was summarized in Figure 4 (Zhang et al, 2016a). …”

Section: Streptomyces Lividans As a Heterologous Hostmentioning

confidence: 99%

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Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

Nepal

Wang

2019

Biotechnology Advances

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Due to the worldwide prevalence of multidrug-resistant pathogens and high incidence of diseases such as cancer, there is an urgent need for the discovery and development of new drugs. Nearly half of the FDA-approved drugs are derived from natural products that are produced by living organisms, mainly bacteria, fungi, and plants. Commercial development is often limited by the low yield of the desired compounds expressed by the native producers. In addition, recent advances in whole genome sequencing and bioinformatics have revealed an abundance of cryptic biosynthetic gene clusters within microbial genomes. Genetic manipulation of clusters in the native host is commonly used to awaken poorly expressed or silent gene clusters, however, the lack of feasible genetic manipulation systems in many strains often hinders our ability to engineer the native producers. The transfer of gene clusters into heterologous hosts for expression of partial or entire biosynthetic pathways is an approach that can be used to overcome this limitation. Heterologous expression also facilitates the chimeric fusion of different biosynthetic pathways, leading to the generation of “unnatural” natural products. The genus Streptomyces is especially known to be a prolific source of drugs/antibiotics, its members are often used as heterologous expression hosts. In this review, we summarize recent applications of Streptomyces species, S. coelicolor, S. lividans, S. albus, S. venezuelae and S. avermitilis, as heterologous expression systems.

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“…One key issue that is difficult to address, especially for gene clusters for which the real molecular product is unknown beforehand, is that of cross-talk between the heterologously expressed pathway and the native pathways. A recent study by Zhang et al showed that heterologous expression of the lyngbyatoxin gene cluster in three different streptomycete hosts lead to the generation of different natural product derivatives [78]. Because small variations in chemical structure can have a major impact on biological activity, expression studies in multiple hosts (or multiple versions of the same hosts with different native BGCs knocked out using, e.g.…”

Section: Grapementioning

confidence: 99%

Exploration and exploitation of the environment for novel specialized metabolites

Loureiro

Medema

Oost

et al. 2018

Current Opinion in Biotechnology

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Microorganisms are Nature's little engineers of a remarkable array of bioactive small molecules that represent most of our new drugs. The wealth of genomic and metagenomic sequence data generated in the last decade has shown that the majority of novel biosynthetic gene clusters (BGCs) is identified from cultivation-independent studies, which has led to a strong expansion of the number of microbial taxa known to harbour BGCs. The large size and repeat sequences of BGCs remain a bioinformatic challenge, but newly developed software tools have been created to overcome these issues and are paramount to identify and select the most promising BGCs for further research and exploitation. Although heterologous expression of BGCs has been the greatest challenge until now, a growing number of polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS)-encoding gene clusters have been cloned and expressed in bacteria and fungi based on techniques that mostly rely on homologous recombination. Finally, combining ecological insights with state-of-the-art computation and molecular methodologies will allow for further comprehension and exploitation of microbial specialized metabolites.

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Structural Diversification of Lyngbyatoxin A by Host‐Dependent Heterologous Expression of the tleABC Biosynthetic Gene Cluster

Cited by 13 publications

References 32 publications

A pharmaceutical model for the molecular evolution of microbial natural products

A pharmaceutical model for the molecular evolution of microbial natural products

Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products

Exploration and exploitation of the environment for novel specialized metabolites

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