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Tag Archives: Synthetic Biology
“Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin” Westfall, P.J.; Pitera, D.J.; Lenihan, J.R.; Eng, D.; Woolard, F.X.; Regentin, R.; Horning, T.; Tsuruta, H.; Melis, D.J.; Owens, A.; Fickes, S.; Diola, D.; Benjamin, K.R.; Keasling, J.D.; Leavell, M.D.; McPhee, D.J.; Renninger, N.S.; Newman, J.D.; Paddon, C.J. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, E111-E118. DOI: 10.1073/pnas.1110740109.
Malaria, caused mainly by the parasite Plasmodium falciparum, leads to nearly a million deaths and 250 million new infections each year. The sesquiterpene lactone endoperoxide artemisinin, derived from Artemisia annua, is very effective as an antimalarial drug, and widespread resistance hasn’t yet developed. Artemisinin is the only high-volume drug that is still isolated by extraction from its native plant producer in a low-yielding (around 10 μg per g plant material), resource-intensive process that uses volatile solvents (most commonly hexane).
As a result, supplies of the drug are short, and those who need it often can’t afford it. The development of new processes for artemisinin production would therefore advance both public health and green chemistry interests. Total synthesis of the drug hasn’t been considered as a viable alternative because of low yields, but a lot of effort has been directed toward developing semi-synthetic sources of artemisinin using a combination of microbial fermentation and chemical synthesis. Toward this end, the Keasling lab reported a few years ago that they had constructed a biosynthetic pathway for the artemisinin precursor amorpha-4,11-diene in yeast with yields of ~200 mg/L—already impressive given the complexity of the molecule. Amorphadiene synthase (ADS) comes from Artemisia annua; the rest of the genes are from yeast. Here is the existing pathway:
“Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol” Yim, H.; Haselbeck, R.; Niu, W.; Pujol-Baxley, C.; Burgard, A.; Boldt, J.; Khandurina, J.; Trawick, J. D.; Osterhout, R. E.; Stephen, R.; Estadilla, J.; Teisan, S.; Schreyer, H.B.; Andrae, S.; Yang, T. H.; Lee, S. Y.; Burk, M. J.; Van Dien, S. Nature Chem. Bio. 2011. 7, 445-452. DOI: 10.1038/nchembio.580
The production of chemicals from biologically-derived feedstocks is a major goal of green chemistry research, but despite a lot of work that’s been done, it’s going to be hard to make the switch from petroleum-derived chemicals to bio-based ones. This is especially true for high-volume commodity chemicals – many of these chemicals have been produced from petroleum for a hundred years, the processes have been optimized to work efficiently on enormous scale, and they are really, really cheap. So the bar is set pretty high, and most papers from academic labs on microbial or enzymatic chemical production are too low-yielding to ever be commercialized (although to be fair, the same could be said for most synthetic chemistry papers). That’s why I was a drawn to this paper published by Genomatica, a company based in San Diego, on the production of 1,4-butanediol by an engineered strain of E. coli – first they got the bug to produce 1,4-butanediol, then they engineered it to produce lots of the stuff. Currently one million tons of 1,4-butanediol (BDO) are produced each year, virtually all of it derived from petroleum-based feedstock chemicals.
Apparently 40% of this is used in the production of Spandex, and the rest of it is used to make other polymers and THF. If Genomatica’s BDO production works according to their plan, all those tons of spandex could be bio-based!