BIOBASED CHEMICALS
and to separate it from other endogenous metabolites
• Fluctuating yields , due to environmental factors like pests , diseases , weather and drought6 As agricultural production is often geographically limited by suitable climate for cultivating the host plant , transportation and political stability are key determinants of supply chain resilience . Transporting raw materials or intermediates may increase overall costs and necessitate the establishment of strategic reserves . These factors often lead to severely limited availability of plant-derived medication , mostly in developing countries .
To circumvent the uncertainties and mitigate the risks associated with agricultural production , farming-independent production technologies are the focus of research . Two typical alternatives are chemical synthesis and metabolic engineering to reconstitute entire plant metabolic pathways in genetically modified microbes , such as Escherichia coli and yeast species .
Chemical synthesis
The economic success of chemical synthesis of plant-derived pharmaceuticals largely depends on the stereochemical complexity of the target molecule . The complex stereochemical structure of these compounds makes it challenging
to provide an economically viable production alternative .
The abundance of chiral carbon atoms in our selected molecules necessitates the use of complex feedstocks , and advanced chemical or chemo-enzymatic synthesis strategies to achieve their full synthesis . Although several synthesis routs have been developed for artemisinin , and paclitaxel , none has yet become an economically viable alternative . 6 , 7
One strategy to circumvent this problem is the development of functional analogues with a simpler chemical structure . Such a strategy is represented by several synthetic drugs , such as the anti-malarial chloroquine . Due to the lack of chiral carbon atoms , the chemical synthesis of such compounds is less challenging .
Metabolic engineering
Metabolic engineering aims to transfer entire biosynthesis pathways into genetically modified microbes . This strategy is made possible by the identification of enzyme cascades in biosynthetic pathways and immense development on the field of biotechnology .
Although the production of numerous plant-derived pharmaceuticals has been demonstrated in engineered microbial hosts , in most cases low yield of the target molecule inhibits economic viability . 8 Artemisinin is an outstanding example where production became economically viable using a semisynthetic approach : artemisinic acid is produced in yeast and converted into artemisinin by a final chemical conversion . 9
The low success rate of this strategy points out the challenges of transferring multi-step enzymatic pathways into foreign hosts , for several reasons . Firstly , it is difficult to maintain effective carbon flow towards the introduced biosynthetic pathway .
In addition , the expression of P450- type cyclooxygenases is difficult in microbial hosts at the same time these enzymes are prevalent in plant metabolism . 10 , 11 Finally , enzymes of metabolic pathways are often clustered or organised spatially to ensure effective handover of intermediates , which is difficult to re-establish for the transferred enzymes in the microbial host . 5
The alternative : Production using cultured plant cells
A promising and viable strategy to produce plant-derived pharmaceutical is based on cultured cells of the host plant producing the target compound or related species . Taxol is a marvellous demonstration of this strategy .
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Pests & disease Political stability & transportation
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Weather Climate change
Figure 2 – Factors affecting agriculturebased production of plant-derived pharmaceuticals
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