Bioengineering natural product biosynthetic pathways for therapeutic applications

Wu, Ming‐Cheng; Law, Brian J. C.; Wilkinson, Barrie; Micklefield, Jason

doi:10.1016/j.copbio.2012.03.008

Cited by 37 publications

(35 citation statements)

References 66 publications

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“…The genome sequences of important Actinobacteria species reported to date indicate that as much as 90% of the chemical potential of these organisms remains undiscovered and that the biosynthetic machinery encoded by many of these genetic loci may be activatable under laboratory conditions (449). The predictive models of Watve et al (450) suggested that over 150,000 bioactive metabolites from members of the genus Streptomyces alone within this order are still waiting to be discovered (328,451).…”

Section: Actinobacteria As Sources Of Bioherbicide and Bioinsecticidementioning

confidence: 99%

Taxonomy, Physiology, and Natural Products of Actinobacteria

Barka

Vatsa

Sanchez

et al. 2016

Microbiol Mol Biol Rev

1,450

1,048

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SUMMARYActinobacteriaare Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. ManyActinobacteriahave a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture.Actinobacteriaplay diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species ofCorynebacterium,Mycobacterium,Nocardia,Propionibacterium, andTropheryma), soil inhabitants (e.g.,MicromonosporaandStreptomycesspecies), plant commensals (e.g.,Frankiaspp.), and gastrointestinal commensals (Bifidobacteriumspp.).Actinobacteriaalso play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum.

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Section: Actinobacteria As Sources Of Bioherbicide and Bioinsecticidementioning

confidence: 99%

Taxonomy, Physiology, and Natural Products of Actinobacteria

Barka

Vatsa

Sanchez

et al. 2016

Microbiol Mol Biol Rev

1,450

1,048

View full text Add to dashboard Cite

show abstract

“…3 The link between the sequence of the genes and the chemical structure of the product is particularly clear for pathways utilizing giant assembly-line synthases to produce complex reduced polyketides or nonribosomally-determined peptides. 4,5 However, there remain a number of valuable chemotypes whose biosynthetic pathways are obscure, and also many orphan clusters whose potentially novel products remain to be elucidated. Methods for systematic analysis of the entire complement of secondary metabolite biosynthetic gene clusters in a strain remain cumbersome and slow.…”

Section: Introductionmentioning

confidence: 99%

A genomics-led approach to deciphering the mechanism of thiotetronate antibiotic biosynthesis

et al. 2016

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“…Engineering targeted changes in modular type I PKSs of prokaryotes generated small, focused libraries of conservative variants of selected bioactive scaffolds. However, these pioneering works with prokaryotic PKSs also yielded many unproductive combinations, suffered from greatly reduced product yields, and realized only a small fraction of the potential chemical space (28)(29)(30)(31).…”

Section: Significancementioning

confidence: 99%

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

Zhou

Zhang

et al. 2014

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

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Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosynthesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery.secondary metabolites | fungal genetics

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Bioengineering natural product biosynthetic pathways for therapeutic applications

Cited by 37 publications

References 66 publications

Taxonomy, Physiology, and Natural Products of Actinobacteria

Taxonomy, Physiology, and Natural Products of Actinobacteria

A genomics-led approach to deciphering the mechanism of thiotetronate antibiotic biosynthesis

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

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