A cell-free platform for the prenylation of natural products and application to cannabinoid production

Meaghan A. Valliere, Tyler P. Korman, Nicholas B. Woodall, Gregory A. Khitrov, Robert E. Taylor, David Baker and James U. Bowie ()
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Meaghan A. Valliere: Molecular Biology Institute, UCLA-DOE Institute, University of California
Tyler P. Korman: Molecular Biology Institute, UCLA-DOE Institute, University of California
Nicholas B. Woodall: Institute for Protein Design, University of Washington
Gregory A. Khitrov: Molecular Biology Institute, UCLA-DOE Institute, University of California
Robert E. Taylor: Molecular Biology Institute, UCLA-DOE Institute, University of California
David Baker: Institute for Protein Design, University of Washington
James U. Bowie: Molecular Biology Institute, UCLA-DOE Institute, University of California

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low natural abundance, alternative production methods are needed. Metabolic engineering enables natural product biosynthesis from inexpensive biomass, but is limited by the complexity of secondary metabolite pathways, intermediate and product toxicities, and substrate accessibility. Alternatively, enzyme catalyzed prenyl transfer provides excellent regio- and stereo-specificity, but requires expensive isoprenyl pyrophosphate substrates. Here we develop a flexible cell-free enzymatic prenylating system that generates isoprenyl pyrophosphate substrates from glucose to prenylate an array of natural products. The system provides an efficient route to cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA) at >1 g/L, and a single enzymatic step converts the precursors into cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA). Cell-free methods may provide a powerful alternative to metabolic engineering for chemicals that are hard to produce in living organisms.

Date: 2019
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DOI: 10.1038/s41467-019-08448-y

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