Metabolic engineering for the production of clinically important molecules: Omega‐3 fatty acids, artemisinin, and taxol

Abstract

Driven by requirements for sustainability as well as affordability and efficiency, metabolic engineering of plants and microorganisms is increasingly being pursued to produce compounds for clinical applications. This review discusses three such examples of the clinical relevance of metabolic engineering: the production of omega-3 fatty acids for the prevention of cardiovascular disease; the biosynthesis of artemisinic acid, an anti-malarial drug precursor, for the treatment of malaria; and the production of the complex natural molecule taxol, an anti-cancer agent. In terms of omega-3 fatty acids, bioengineering of fatty acid metabolism by expressing desaturases and elongases, both in soybeans and oleaginous yeast, has resulted in commercial-scale production of these beneficial molecules. Equal success has been achieved with the biosynthesis of artemisinic acid at low cost for developing countries. This is accomplished through channeling the flux of the isoprenoid pathway to the specific genes involved in artemisinin biosynthesis. Efficient coupling of the isoprenoid pathway also leads to the construction of an Escherichia coli strain that produces a high titer of taxadiene-the first committed intermediate for taxol biosynthesis. These examples of synthetic biology demonstrate the versatility of metabolic engineering to bring new solutions to our health needs.

2C-Methyl-d-erythritol 4-Phosphate Enhances and Sustains Cyclodiphosphate Synthase IspF Activity

“…3–8 In addition, the pathway has the potential to be manipulated through bioengineering methods to enable increased and sustained production of isoprenoids with medicinal value. 31–34 Understanding enzyme function and regulation in the MEP pathway is critical in the endeavor to target these enzymes in the development of new anti-infective agents or optimize isoprenoid production in bioengineering efforts. However, relatively little is known about regulation of the MEP pathway in pathogenic organisms.…”

Advances in Metabolic Engineering of Saccharomyces cerevisiae for the Production of Industrially and Clinically Important Chemicals

“…Terpene derivatives are economically viable molecules that are used in the synthesis of drugs such as the antimalarial agent artemisinin, and the anticancer agent taxol [63]. Several terpenoids have been produced in S. cerevisiae by reconstitution of the relevant biosynthetic pathways.…”

“…The well-known diterpenoid taxol is an anti-cancer agent [63,65]. As a irst step towards taxol production, S. cerevisiae was metabolically engineered for taxadiene biosynthesis [66].…”

Fine-tuning of ecaA and pepc gene expression increases succinic acid production in Escherichia coli

“…The great success of constructing artificial life and producing antimalarial drug artemisinin (Gibson et al 2010;Ro et al 2006;Paddon and Keasling 2014) has aroused more and more attention on synthetic biology. Recently, the studies of synthetic biology have made great progress in the fields of medicine, e.g., the synthesis of antibiotic, antibody, and new treatments (Yeh et al 2009;Langer and Tirrell 2004;Leitao and Engutia 2014), biological energy source, e.g., the alcohol and hydrocarbon production (Hawkins et al 2013;Yang et al 2012;Bi et al 2013;Rabinovitch-Deere et al 2013;Lee et al 2012;Keasling 2010), bio-based chemicals, e.g., the production of succinic acid and fatty acids by engineered bacteria Wang et al 2014a;Ye and Bhatia 2012) and other industrial circles, environmental protection, and agricultural production (Mossman et al 2007;Mayfield 2013). While the focus of the synthetic biology in the above fields is to construct artificial gene regulatory networks in biological systems (Feist and Palsson 2008), accordingly, metabolic network reconstructions have significantly expanded over the past two decades.…”