Synthesizing natural products

While there has been a recent resurgence of interest in natural products as drug candidates, the often complicated scaffolds make it difficult to synthesize these compounds, and yields from natural sources are typically too small for large-scale extraction.

Randall C Willis
SAN DIEGO—While there has been a recent resurgence of interest in natural products as drug candidates, the often complicated scaffolds make it difficult to synthesize these compounds, and yields from natural sources are typically too small for large-scale extraction. In Nature Chemical Biology, however, two groups describe their efforts to harness the power of biosynthetic machinery ex vivo to perform single-pot total synthesis of clinically relevant natural products.
 
In the first paper, researchers at UCSD and the University of Arizona characterized the enzymes and co-factors involved in the production of the bacteriostatic polyketides enterocin and wailupemycin. Isolating the biosynthetic genes from Streptomyces maritimus, the researchers expressed and purified (or purchased) the enzymes needed to generate the polyketides, combining them in a single reaction vessel with substrates and co-factors to produce both compounds at ~25% yields.
 
In the second paper, researchers at Harvard Medical School performed a similar experiment, identifying, cloning, and expressing from Aspergillus nidulans the genes involved in the biosynthesis of the antifungal asterriquinones. In a single reaction vessel, the researchers combined enzymes, co-factors, and substrates to produce terrequinone A and several intermediates.
 
Aside from their value in improving our understanding of biosynthetic pathways and in producing the intended products, the experiments also open the door to the incorporation of non-natural substrates to produce a broader spectrum of compounds that may show potential as novel drugs.

Randall C Willis

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