Biosynthesis of medicinally important plant metabolites by unusual type III polyketide synthases
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REVIEW
Biosynthesis of medicinally important plant metabolites by unusual type III polyketide synthases Ikuro Abe1 Received: 29 April 2020 / Accepted: 13 May 2020 © The Japanese Society of Pharmacognosy 2020
Abstract Recent research progress on the “second generation” type III polyketide synthases is summarized. This class of enzymes catalyzes unusual condensation chemistries of CoA thioesters to generate various core structures of medicinally important plant secondary metabolites, including the R 1–C–R2 scaffold of alkyl quinolones, curcuminoids, as well as the 8-azabicyclo[3.2.1] octane ring of tropane alkaloids. The discovery of this fascinating enzyme superfamily provides excellent opportunities for the manipulation of the enzyme reactions to expand the supply of natural and unnatural molecules for future drug development. Keywords Biosynthesis · Enzyme · Type III polyketide synthase · Curcumin · Quinolone · Tropane alkaloid
Introduction The type III polyketide synthase (PKS) superfamily enzymes generate incredibly diverse core structures of medicinally important plant secondary metabolites, including flavonoids, stilbenes, chromones, pyrones, phloroglucinols, resorcinols, xanthones, acridones, and quinolones (Figs. 1, 2) [1–5]. For example, chalcone synthase (CHS) and stilbene synthase (STS) are plant-specific typical type III PKSs that accept p-coumaroyl-CoA as the starter substrate to catalyze three successive condensations with malonyl-CoA to generate naringenin chalcone and resveratrol, respectively. These enzymes utilize different (Claisen-type or decarboxylative aldol-type) cyclizations of an enzyme-bound, common linear poly-β-keto intermediate (Fig. 2). Recent biochemical and structural investigations have revealed that the homodimeric superfamily enzymes possess a highly homologous overall structure, with a conserved Cys-His-Asn catalytic triad as well as a characteristic CoA-binding tunnel [1–5]. The enzyme reactions are initiated by loading of the starter Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11418-020-01414-9) contains supplementary material, which is available to authorized users. * Ikuro Abe [email protected]‑tokyo.ac.jp 1
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku, Tokyo 113‑0033, Japan
substrate, polyketide chain elongation through decarboxylative condensation with the extender substrate, and termination by cyclization of the resulting intermediate, within a single active site. The prominent diversity of the functions of these highly homologous enzymes is attributed to the slight differences in the volume and architecture of the active site cavity, which determine the preference for the starter and extender substrates, the number of chain elongation reactions, and the mode of cyclization reactions [1–5]. This short review focuses on the recently reported unusual “second generation” type III PKS enzymes [5], which mediate the fascinating chemistry of condensation reactions of CoA t
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