Biosynthesis of 3-hydroxybenzoate-derived polyketides in Gentianaceae
Final Report Abstract
Plants produce a diversity of natural products, which exhibit a range of interesting biological activities. For a long time, plant constituents have been exploited by humans as source of drugs and they continue to play an important role in drug discovery. Either genuine drug substances or semisynthetic derivatives and synthetic analogues are used. A major group of plant-derived natural products consists of polyketides. These compounds are formed by a superfamily of enzymes, called type III polyketide synthase (PKS) proteins. These enzymes catalyse the condensation of multiple acetyl units from the decarboxylation of malonyl-CoA with a specific starter unit. Variation of either the starter substrate or the number of condensation steps and the type of intramolecular cyclization leads to the amazing diversity of polyketide products. The prototype enzyme of the superfamily is chalcone synthase, which initiates flavonoid biosynthesis. We studied PKSs that use benzoyl-CoA as the starter substrate. Benzophenone synthase forms the skeleton of polyprenylated benzophenones and xanthones, which are pharmacologically intriguing constituents mainly found in Hypericaceae. Biphenyl synthase provides the scaffold of biphenyls and dibenzofurans, which serve as defence compounds of apple and pear (Rosaceae). In Gentianaceae, the starter for PKSs is a 3-hydroxylated substrate. Biphenyl carboxylate synthase forms amarogentin, which is the bitterest natural product. Benzophenone synthases from Gentianaceae prefer a starter substrate with even three 3-hydroxybenzoyl residues. We isolated transcripts for a number of PKSs that use (3-hydroxy)benzoyl-CoA. The molecular and kinetic properties of these enzymes were determined. The effects of single and multiple mutations were studied. Crystallization of the enzymes to gain structural insights was challenging. Our results contribute to both the fundamental understanding of plant polyketide biosynthesis and the development of strategies for biotechnological production of promising polyketide compounds.
Publications
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Benzophenone Synthase and Chalcone Synthase Accumulate in the Mesophyll of Hypericum perforatum Leaves at Different Developmental Stages. Frontiers in Plant Science, 7(2016, 6, 29).
Belkheir, Asma K.; Gaid, Mariam; Liu, Benye; Hänsch, Robert & Beerhues, Ludger
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Biotechnological Production of Prenylated Xanthones for Pharmaceutical Use. Pharmaceutical Biocatalysis (2019, 11, 7), 103-142. Jenny Stanford Publishing.
Gaid, Mariam; Singh, Poonam; El-Awaad, Islam; Nagia, Mohamed & Beerhues, Ludger
