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Review
. 2012 Oct;23(5):736-43.
doi: 10.1016/j.copbio.2011.12.016. Epub 2012 Jan 3.

Synthetic biological approaches to natural product biosynthesis

Jaclyn M Winter  1 , Yi Tang
Affiliations
Review

Synthetic biological approaches to natural product biosynthesis

Jaclyn M Winter et al. Curr Opin Biotechnol. 2012 Oct.

Abstract

Small molecules produced in Nature possess exquisite chemical diversity and continue to be an inspiration for the development of new therapeutic agents. In their host organisms, natural products are assembled and modified using dedicated biosynthetic pathways. By rationally reprogramming and manipulating these pathways, unnatural metabolites containing enhanced structural features that were otherwise inaccessible can be obtained. Additionally, new chemical entities can be synthesized by developing the enzymes that carry out these complicated chemical reactions into biocatalysts. In this review, we will discuss a variety of combinatorial biosynthetic strategies, their technical challenges, and highlight some recent (since 2007) examples of rationally designed metabolites, as well as platforms that have been established for the production and modification of clinically important pharmaceutical compounds.

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Figures

Figure 1
Figure 1
Strategies for combinatorial biosynthesis. A) Engineering the production of fluorosalinosporamide in Salinospora tropica by replacing the chlorinase gene salL with the fluorinase gene flA from Streptomyces catteleya; B) Formation of glycosylated streptolvdigin derivatives by expressing genes coding for several deoxyhexoses in a mutant strain lacking the ability to produce its innate deoxyhexose moiety; C) Production of kanamycin derivatives by heterologously expressing different combinations of biosynthetic genes from Streptomyces kanamyceticus in the non-aminoglycoside-producing Streptomyces venezuelae host.
Figure 2
Figure 2
Reprogramming polyketide megasynthases through rational domain swapping. A) Formation of doramectin in Streptomyces avermitilis by replacing the loading module of the avermectin PKS with the cyclohexanecarboxylic (CHC) loading module from phoslactomycin PKS; B) Production of an unnatural natural product in Aspergillus nidulans by swapping the SAT domain of the asperfuranone PKS with the sterigmatocystin SAT; C) Biosynthesis of aromatic bacterial polyketides in Escherichia coli using an engineered fungal PKS and bacterial cyclase.
Figure 3
Figure 3
Examples of unnatural natural products created through combinatorial biosynthesis.
Figure 4
Figure 4
Engineered production of halogenated metabolites in Catharanthus roseus.
See this image and copyright information in PMC

References

    1. Li JW, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science. 2009;325:161–165. - PubMed
    1. Carter GT. Natural products and Pharma 2011: strategic changes spur new opportunities. Nat Prod Rep. 2011;28:1783–1789. - PubMed
    1. Kennedy J. Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. Nat Prod Rep. 2008;25:25–34. - PubMed
    1. Brakhage AA, Schroeckh V. Fungal secondary metabolites - strategies to activate silent gene clusters. Fungal Genet Biol. 2011;48:15–22. - PubMed
    1. Chen Y, Smanski MJ, Shen B. Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation. Appl Microbiol Biotechnol. 2010;86:19–25. - PMC - PubMed

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