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Publications - Cell and Metabolic Biology
Publications
Diterpenoids form a diverse group of natural products, many of which are or could become pharmaceuticals or industrial chemicals. The modular character of diterpene biosynthesis and the promiscuity of the enzymes involved make combinatorial biosynthesis a promising approach to generate libraries of diverse diterpenoids. Here, we report on the combinatorial assembly in yeast of ten diterpene synthases producing (+)-copalyldiphosphate-derived backbones and four cytochrome P450 oxygenases (CYPs) in diverse combinations. This resulted in the production of over 200 diterpenoids. Based on literature and chemical database searches, 162 of these compounds can be considered new-to-Nature. The CYPs accepted most substrates they were given but remained regioselective with few exceptions. Our results provide the basis for the systematic exploration of the diterpenoid chemical space in yeast using sequence databases.
Publications
Sesquiterpene lactones (STLs) are bitter tasting plant specialized metabolites derived from farnesyl pyrophosphate (FPP) that contain a characteristic lactone ring. STLs can be found in many plant families that are distantly related to each other and outside the plant kingdom. They are especially prevalent in the plant families Apiaceae and Asteraceae, the latter being one of the largest plant families besides the Orchidaceae. The STL diversity is especially large in the Asteraceae, which made them an ideal object for chemosystematic studies in these species. Many STLs show a high bioactivity, for example as protective compounds against herbivory. STLs are also relevant for pharmaceutical applications, such as the treatment of malaria with artemisinin. Recent findings have dramatically changed our knowledge about the biosynthesis of STLs, as well as their developmental, spatial, and environmental regulation. This review intents to update the currently achieved progress in these aspects. With the advancement of genome editing tools such as CRISPR/Cas and the rapid acceleration of the speed of genome sequencing, even deeper insights into the biosynthesis, regulation, and enzyme evolution of STL can be expected in the future. Apart from their role as protective compounds, there may be a more subtle role of STL in regulatory processes of plants that will be discussed as well.
Publications
The pyrethrum plant, Tanacetum cinerariifolium (Asteraceae) synthesizes a class of compounds called pyrethrins that have strong insecticidal properties but are safe to humans. Class I pyrethrins are esters of the monoterpenoid trans-chrysanthemic acid with one of three jasmonic-acid derived alcohols. We reconstructed the trans-chrysanthemic acid biosynthetic pathway in tomato fruits, which naturally produce high levels of the tetraterpene pigment lycopene, an isoprenoid which shares a common precursor, dimethylallyl diphosphate (DMAPP), with trans-chrysanthemic acid. trans-Chrysanthemic acid biosynthesis in tomato fruit was achieved by expressing the chrysanthemyl diphosphate synthase gene from T. cinerariifolium, encoding the enzyme that uses DMAPP to make trans-chrysanthemol, under the control of the fruit specific promoter PG, as well as an alcohol dehydrogenease (ADH) gene and aldehyde dehydrogenase (ALDH) gene from a wild tomato species, also under the control of the PG promoter. Tomato fruits expressing all three genes had a concentration of trans-chrysanthemic acid that was about 1.7-fold higher (by weight) than the levels of lycopene present in non-transgenic fruit, while the level of lycopene in the transgenic plants was reduced by 68%. Ninety seven percent of the diverted DMAPP was converted to trans-chrysanthemic acid, but 62% of this acid was further glycosylated. We conclude that the tomato fruit is an alternative platform for the biosynthesis of trans-chrysanthemic acid by metabolic engineering.
This page was last modified on 27 Jan 2025 .
