Rational design of carbon skeleton by bioengineering Towards synthesis and pharmaceutical application of compounds not found in nature
Researchers at the University of Tokyo have demonstrated a new biosynthetic methodology to rationally design the polyketide carbon skeleton of the antibiotic antimycin. The findings open the door to the biosynthetic production of “unnatural” natural products, which will contribute to medicinal chemistry.
The synthesis of pharmaceuticals is mostly performed by organic synthesis. Recently, however, much attention has been focused on synthetic biology, which produces valuable compounds by enzymatic reaction and microbial fermentation. However, there are still only limited ways to rationally design a target compound by synthetic biology, thus the invention of methodologies that enable free molecular design has been a major challenge.
The research group of Ph.D student Lihan Zhang and Professor Ikuro Abe at the University of Tokyo Graduate School of Pharmaceutical Sciences has successfully introduced an aromatic substitution into the carbon skeleton of a polyketide antibiotic, antimycin. The research group focused on an enzyme, crotonyl-CoA carboxylase/reductase, which supplies building blocks of the carbon skeleton, and enhanced the catalytic property of the enzyme to provide unnatural building blocks that are not seen in natural poliketides. Furthermore, by introducing the engineered enzyme into biosynthesis of antimycin, unnatural compounds with novel carbon skeletons bearing aromatic residues were produced.
“One of the feature of natural products is that they utilize common strategies to build diverse molecules, and hence this result could be theoretically applicable to the biosynthesis of many natural products,” says Professor Abe. By diversifying the structures of natural products that are hard to synthesize, the findings demonstrated here will lead to developments in drug discovery.
Rational Control of Polyketide Extender Units by Structure-based Engineering of a Crotonyl-CoA Carboxylase/Rreductase in Antimycin Biosynthesis", Angewandte Chemie International Edition 2015/9/10: Online Edition (Japan time), doi: 10.1002/ange.201506899.
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