Sesquiterpenoids - Biosynthesis and Applied combinatorial biochemistry

Plant cells are capable of producing an overwhelming variety of secondary metabolites among others sesquiterpenoids, both in terms of complexity and quantity. Sesquiterpenoids allow plants to cope with various types of stress, and often also have biological activities of high interest to human industries. We aim at making this overwhelming variety economically accessible by introducing the biosynthesis of interesting natural products from higher plants into the primitive moss Physcomitrella patens.
 
Knowledge of the biosynthesis of natural products in focus or similar structures will be obtained from the plant of origin or closely related species, we are mainly working with plants from the Apiaceae family. The biosynthetic enzymes will be introduced into Physcomitrella to obtain either the natural product of interest or a precursor for chemical synthesis.
 
The moss Physcomitrella is the ideal candidate for the production of the difficult accessible natural products. This simple plant can be maintained in an undifferentiated protonemal state in liquid cultures. It grows efficiently in a cheap and simple media when supplied with adequate light and can be maintained in large quantities in bioreactors. Unlike other known plant models, Physcomitrella enables high efficient homologous recombination (Schaefer, Annu. Rev. Plant. Biol. 53:477-501, 2002). This permits us to make specific and controlled recombination events and to generate transformants with predictable properties. Thus, stable production strain development neither requires crossing steps nor regeneration of whole plants.
 
Combinatorial biochemistry involves interchanging 'metabolism' genes between organisms to create unnatural gene combinations or hybrid genes. Novel metabolites can be made due to the effect of new enzyme-metabolic pathway combinations or to the formation of proteins with new enzymatic properties.

Combinatorial biosynthesis has already been successfully employed in micro-organisms, e.g. for the production of novel antibiotics. An in vivo combinatorial biosynthesis approach is pursued in Physcomitrella, primarily to obtain new or known sesquiterpeniods. The technology platform developed in our lab will offer the opportunity to browse into the entire metabolic repertoire of a plant and to assess the principle of combinatorial biosynthesis in plant cells and transfer these into Physcomitrella.

Cross disciplinary research projects draw upon expertise within the biochemistry lab as a whole, and on a great variety of external research partners. We aim at targeting several either upcoming or already established drugs of sesquiterpene origin.