Health and Synthetic Biology – V
Translation by J. R. Aguilar Cosme
Vaccines and drugs
Metabolic engineering
Inside cells, chemical substances are transformed by enzymes into a great variety of products that can be used as beneficial drugs. Nevertheless, many of these products are not always necessary for the survival of the organism and are generally produced in reduced quantities. Furthermore, some metabolic pathways are also exclusive to a single type of organism,and are often difficult to reproduce on a larger scale.
Metabolic engineering is the discipline in charge of studying, modifying and optimizing the metabolic pathways of various organisms to produce specific substances with greater efficiency and reduced costs.
Terpenoids
Dr. Keaslings’s group in the University of California at Berkeley has spent several years applying the concepts of Synthetic Biology to the Metabolic Engineering of organisms. Some of their more interesting works are the ones related to the Metabolic Engineering of terpenoids and P450 cytochromes.
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| From Ro, et al., (2006) |
Terpenoids are a family of secondary metabolites in plants, among which are some important drugs, such as taxol – used as a chemotherapeutic against cancer- and artemisinin – used to treat malaria.
In 2006, Dr. Keasling and his team published their research on a particular yeast strain capable of producing artemisinic acid, one of the precursors to artemisinin. The researchers introduced and overexpressed some of the genes involved on mevalonate biosynthesis -the pathway that leads to the biosynthesis of artemisinin- and modified some of the yeast genes to increase the metabolic flux to limit the interference of alternative routes to finally redirect the yeast’s metabolism towards the production of artemisinic acid.
The possibilities of producing artemisinin via semi-synthetic means – in this case, starting with proper metabolic precursors obtained from an organism- represent a very attractive alternative when faced with the reported shortage of the compound that is produced from its natural source, the plant Artemisia annua, and the high processing costs of complete artificial synthesis.
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| From Ajikumar, et al., (2010) |
In a more recent publication, a group of researchers - Dr. Keasling among them- from the UCB developed a yeast strain capable of producing amorpha-4,11-diene, an intermediary that precedes artemisinic acid, in levels of up to 40 g/L, after the overexpression of all the genes in the mevalonic acid pathway. During the development of this strain, it was observed that even though the biosynthesis of artemisinic acid was possible, the production of amorpha-4,11-diene yielded better results. The researchers also reported a chemical method for the production of artemisinin using amorpha-4,11-diene.
In the case of other terpenoids, the Metabolic Engineering of other precursors of taxol has been addressed in E. coli by P.K. Ajikumar and colleagues, who have reported taxadiene production of up to 300 mg/L. This was achieved after systematically modifying expression levels of one of the bacteria’s own pathways, and also using a series of heterologous enzymes. Lycopene production, as an antioxidant, has also been adapted to an E. coli chassis.
