Metabolic engineering of cyclic triterpenoid production in Saccharomyces cerevisiae

Topic

Pathway Scale Engineering

Authors

Birgitta E. Ebert, iAMB - Institute of Applied Microbiology, RWTH Aachen University, Aachen, Germany

Kerstin Walter, iAMB - Institute of Applied Microbiology, RWTH Aachen University, Aachen, Germany
Christine Lang, Organobalance GmbH, Berlin
Lars M. Blank, iAMB - Institute of Applied Microbiology, RWTH Aachen University, Aachen, Germany

Abstract

Triterpenoids are terpenoids derived from squalene and consist of six isoprene units (C30). These compounds can be isolated from many different plant sources. They occur in countless variations and can be subclassified into several groups including squalenes, lanostanes, dammaranes, lupanes, oleananes, ursanes, hopanes, cycloartanes, friedelanes, cucurbitacins, and miscellaneous compounds (Mullauer et al. 2010). Many of them or their synthetic derivatives are currently being investigated as medicinal products for various diseases, including cancer. Despite their obvious interest for the industry, their wide applications are often hindered by the presence of these compounds in only minute amounts in natural sources. This poses challenges in a biosustainable production of such compounds since per gram active ingredient produced a high volume of solvent is needed in the purification process.
Within the project TRITERP we establish a biotechnological process for the production of betulinic acid, a cyclic triterpenoid, using tailored Saccharomyces cerevisiae strains. The plant metabolite betulinic acid has antiretroviral, antimalarial, and anti-inflammatory properties and has potential as an anticancer agent and is of high interest for the pharmaceutical and nutritional industry (Muffler et al. 2011).
The strain re-engineering is accomplished using advanced and modern molecular biology and synthetic biology tools and taking advantage of the genome-scale science, i.e. applying omics technologies for in depth physiological strain characterization and metabolic modeling for data analysis and strain design.
High overproduction of the triterpenoid will reduce downstream processing efforts and will allow the economic and sustainable production of this promising compound.

The project TRITERP is carried out in collaboration with the Novo Nordisk Foundation Center for Biosustainability (CFB) at the Technical University of Denmark and financed by the DBU â?? Deutsche Bundesstiftung Umwelt (Germany).

References

Muffler K, Leipold D, Scheller MC, Haas C, Steingroewer J, Bley T, Neuhaus HE, Mirata MA, Schrader J, Ulber R. 2011. Biotransformation of triterpenes. Process Biochemistry 46(1):1-15.
Mullauer FB, Kessler JH, Medema JP. 2010. Betulinic acid, a natural compound with potent anticancer effects. Anti-Cancer Drugs 21(3):215-227.